Pyrimidinone derivatives as cdc7 inhibitors

ABSTRACT

The present invention relates to compounds of formula I as defined herein, and salts and solvates thereof, that function as inhibitors of cell division cycle 7 (Cdc7) kinase enzyme activity. The present invention also relates to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which Cdc7 kinase activity is implicated.

INTRODUCTION

This application relates to compounds of Formula I as defined herein andsalts or solvates thereof.

The compounds of Formula I and their salts have Cdc7 inhibitoryactivity, and may be used to treat diseases or conditions mediated, atleast in part, by Cdc7.

The present application further provides pharmaceutical compositionscomprising a compound of Formula I and/or a pharmaceutically acceptablesalt or solvate thereof and an pharmaceutically acceptable excipient.

The present application also provides methods of treating a disease orcondition mediated, at least in part, by Cdc7 in a subject in needthereof comprising administering to the subject a compound of Formula Iand/or a pharmaceutically acceptable salt or solvate thereof.

BACKGROUND OF THE INVENTION

Eukaryotic cells divide by a directed, highly regulated step-wiseprocess known as the cell cycle. DNA replication is an essential part ofcell cycle progression and tight regulation ensures that DNA isreplicated accurately only once during S-phase. In mammalian cells DNAreplication is initiated at multiple sites (origins of replication).Numerous pre-replication complexes (pre-RC) form at origins ofreplication along each DNA strand during G1 to ensure that the wholegenome is completely replicated in S-phase. The inactive pre-RC consistsof the heterohexamer helicase complex Minichromosome maintenance 2-7(MCM2-7), Cell division cycle 6 (Cdc6) and Chromatin licensing and DNAreplication factor 1 (Cdtl) (Donaldson et al., 1998; Masai et al.,2002). Cell division cycle 7 (Cdc7) is a Ser/Thr kinase, which togetherwith its regulatory partner Dumbbell former 4 (Dbf4), forms the activeS-phase kinase complex, Dbf4 dependent kinase (DDK) (Kumagai et al.,1999; Jiang et al., 1999; Duncker et al., 2003). DDK is essential incontrolling the initiation of DNA replication in combination withCdk/cyclins by activation or licensing of the pre-RC; this activationinvolves phosphorylation of MCM2 and MCM4 (Kim 2003, Bousset et al.,1998, Takeda et al., 2001; Bruck et al., 2009; Francis et al., 2009;Sheu et al., 2006; Sheu et al., 2010). Cdc7 phosphorylates MCM2 atvarious sites, including Ser53 and Ser40 exclusively (Charych et al.,2008; Tsuji et al., 2006; Montagnoli et al., 2006; Cho et al., 2006).The phosphorylation of the amino-terminus of MCM4 by Cdc7 is alsoessential for replication, but the exact phoshorylation sites areunknown (Masai et al., 2006; Pereverzeva et al., 2000).

Cdc7 depletion by siRNA inhibits phosphorylation of MCM2 in bothnon-transformed primary fibroblasts and cancer cell lines, howevernon-transformed primary fibroblast cells arrest in G1 whereas cancercells apoptose (Rodriguez-Acebes et al., 2010; Kulkarni et al., 2009.,Montagnoli et al., 2004). The lack of cell death in normal cells isbelieved to be due to the induction of a functioning G1 checkpoint whichis deficient in cancer cell lines. Thus, when Cdc7 is depleted, cancercells enter a defective S-phase and undergo apoptosis due to checkpointdysfunction (Tudzarova et al., 2010; Im et al., 2008; Shreeram et al.,2002). Cdc7 depletion by siRNA in combination with hydroxyurea oretoposide treatment impairs hyper-phosphorylation of Mcm2 at specificCdc7-dependent phosphorylation sites and drug-inducedhyper-phosphorylation of chromatin-bound Mcm4. Indeed, sustainedinhibition of Cdc7 in the presence of hydroxyurea or etoposide increasescell death supporting the notion that the Cdc7 kinase plays a role inmaintaining cell viability during replication stress (Tenca et al.,2007).

In a panel of 62 cancer cell lines Cdc7 protein expression was found tobe increased in ˜50% human tumour cell lines examined, whereas, Cdc7protein was very low or undetectable in normal tissues and cell lines.In addition most of the cancer cell lines with increased Cdc7 proteinlevels also had increased Dbf4 abundance and a high expression of Cdc7protein was also detected in primary breast, colon, and lung tumours butnot in the matched normal tissues (Bonte et al., 2008). Analysis oftumour samples from breast and ovarian cancers have shown a correlationbetween overexpression of Cdc7 and poor survival, tumour grade, geneticinstability and aneuploidy (Rodriguez-Acebes et al., 2010; Kulkarni etal., 2009; Choschzick et al., 2010), supporting the importance of Cdc7in regulating cellular proliferation. Moreover, Cdc7-Dbf4 isoverexpressed in oral squamous cell carcinoma and expression ispositively associated with poor clinical outcome and enhances resistanceto the DNA-damaging cytotoxic agents such as hydroxyurea andcamptothecin (Cheng et al., 2013).

The observation that siRNA mediated knockdown of Cdc7 results inapoptosis in multiple cancer cell lines but not in normal cells makesCdc7 an attractive cancer target. Moreover, inhibition of Cdc7 catalyticactivity has been demonstrated to result in apoptotic cell death inmultiple cancer cell types and tumour growth inhibition in preclinicalcancer models (Montagoli et al., 2008). Furthermore, inhibition of Cdc7blocks DNA synthesis, prevents the activation of replication origins butdoes not impede replication fork progression and does not trigger asustained DNA damage response (Montagoli et al., 2008). Taken togetherthese studies suggest selective inhibition of Cdc7 to be a promisinganticancer therapeutic.

There is a need in the art for agents (alternative and/or improved)capable of inhibiting Cdc7.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound as definedherein, and/or a salt or solvate thereof.

In another aspect, the present invention provides a pharmaceuticalcomposition which comprises a compound as defined herein, or apharmaceutically acceptable salt or solvate thereof, and one or morepharmaceutically acceptable excipients.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in therapy.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the treatmentof a proliferative condition.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the treatmentof cancer.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the productionof a Cdc7 inhibitory effect.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in the treatment ofa proliferative condition.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in the treatment ofcancer.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in the production ofa Cdc7 inhibitory effect.

In another aspect, the present invention provides a method of inhibitingCdc7 in vitro or in vivo, said method comprising contacting a cell withan effective amount of a compound as defined herein, or apharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of inhibitingcell proliferation in vitro or in vivo, said method comprisingcontacting a cell with an effective amount of a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of treating aproliferative disorder in a patient in need of such treatment, saidmethod comprising administering to said patient a therapeuticallyeffective amount of a compound as defined herein, or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical composition asdefined herein.

In another aspect, the present invention provides a method of treatingcancer in a patient in need of such treatment, said method comprisingadministering to said patient a therapeutically effective amount of acompound as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition as defined herein.

In another aspect, the present invention provides a combinationcomprising a compound, or a pharmaceutically acceptable salt or solvatethereof, as defined herein, with one or more additional therapeuticagents.

Preferred, suitable, and optional features of any one particular aspectof the present invention are also preferred, suitable, and optionalfeatures of any other aspect.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The compounds and intermediates described herein may be named accordingto either the IUPAC (International Union for Pure and Applied Chemistry)or CAS (Chemical Abstracts Service) nomenclature systems. It should beunderstood that unless expressly stated to the contrary, the terms“compounds of Formula I”, “compounds of Formula Ib”, “compounds ofFormula Ic” and the more general term “compounds” refer to and includeany and all compounds described by and/or with reference to Formula I,Ib and Ic respectively. It should also be understood that these termsencompasses all stereoisomers, i.e. cis and trans isomers, as well asoptical isomers, i.e. R and S enantiomers, of such compounds and allsalts thereof, in substantially pure form and/or any mixtures of theforegoing in any ratio. This understanding extends to pharmaceuticalcompositions and methods of treatment that employ or comprise one ormore compounds of the Formula I, Ib and Ic, either by themselves or incombination with additional agents.

The various hydrocarbon-containing moieties provided herein may bedescribed using a prefix designating the minimum and maximum number ofcarbon atoms in the moiety, e.g. “(C_(a)-C_(b))”. For example,(C_(a)-C_(b))alkyl indicates an alkyl moiety having the integer “a” tothe integer “b” number of carbon atoms, inclusive. Certain moieties mayalso be described according to the minimum and maximum number of memberswith or without specific reference to a particular atom or overallstructure. For example, the terms “a to b membered ring” or “havingbetween a to b members” refer to a moiety having the integer “a” to theinteger “b” number of atoms, inclusive.

“About” when used herein in conjunction with a measurable value such as,for example, an amount or a period of time and the like, is meant toencompass reasonable variations of the value, for instance, to allow forexperimental error in the measurement of said value.

As used herein by themselves or in conjunction with another term orterms, “alkyl” and “alkyl group” refer to a branched or unbranchedsaturated hydrocarbon chain. Unless specified otherwise, alkyl groupstypically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-4carbon atoms or 1-3 carbon atoms, and can be substituted orunsubstituted. Representative examples include, but are not limited to,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl,tert-butyl, isobutyl, etc.

As used herein by themselves or in conjunction with another term orterms, “alkylene” and “alkylene group” refer to a branched or unbranchedsaturated hydrocarbon chain. Unless specified otherwise, alkylene groupstypically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-3carbon atoms, and can be substituted or unsubstituted. Representativeexamples include, but are not limited to, methylene (—CH₂—), theethylene isomers (—CH(CH₃)— and —CH₂CH₂—), the propylene isomers(—CH(CH₃)CH₂—, —CH(CH₂CH═)-, —C(CH₃)═-, and —CH₂CH₂CH₂—), etc.

As used herein by themselves or in conjunction with another term orterms, “alkenyl” and “alkenyl group” refer to a branched or unbranchedhydrocarbon chain containing at least one double bond. Unless specifiedotherwise, alkenyl groups typically contain 2-10 carbon atoms, such as2-6 carbon atoms or 2-4 carbon atoms, and can be substituted orunsubstituted. Representative examples include, but are not limited to,ethenyl, 3-buten-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl.

As used herein by themselves or in conjunction with another term orterms, “alkynyl” and “alkynyl group” refer to a branched or unbranchedhydrocarbon chain containing at least one triple bond. Unless specifiedotherwise, alkynyl groups typically contain 2-10 carbon atoms, such as2-6 carbon atoms or 2-4 carbon atoms, and can be substituted orunsubstituted. Representative examples include, but are not limited to,ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl.

As used herein by itself or in conjunction with another term or terms,“aromatic” refers to monocyclic and polycyclic ring systems containing4n+2 pi electrons, where n is an integer. Aromatic should be understoodas referring to and including ring systems that contain only carbonatoms (i.e. “aryl”) as well as ring systems that contain at least oneheteroatom selected from N, O or S (i.e. “heteroaromatic” or“heteroaryl”). An aromatic ring system can be substituted orunsubstituted.

As used herein by itself or in conjunction with another term or terms,“non-aromatic” refers to a monocyclic or polycyclic ring system havingat least one double bond that is not part of an extended conjugated pisystem. As used herein, non-aromatic refers to and includes ring systemsthat contain only carbon atoms as well as ring systems that contain atleast one heteroatom selected from N, O or S. A non-aromatic ring systemcan be substituted or unsubstituted.

As used herein by themselves or in conjunction with another term orterms, “aryl” and “aryl group” refer to phenyl and 7-15 memberedbicyclic or tricyclic hydrocarbon ring systems, including bridged,spiro, and/or fused ring systems, in which at least one of the rings isaromatic. Aryl groups can be substituted or unsubstituted. Unlessspecified otherwise, an aryl group may contain 6 ring atoms (i.e.,phenyl) or a ring system containing 9 to 15 atoms, such as 9 to 11 ringatoms, or 9 or 10 ring atoms. Representative examples include, but arenot limited to, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthalenyl,6,7,8,9-tetrahydro-5H-benzocycloheptenyl, and6,7,8,9-tetrahydro-5H-benzocycloheptenyl. Suitably an aryl group isphenyl.

As used herein by themselves or in conjunction with another term orterms, “arylene” and “arylene group” refer to a phenylene (—C₆H₄—) or to7 to 15 membered bicyclic or tricyclic hydrocarbon ring systems,including bridged, spiro, and/or fused ring systems, in which at leastone of the rings is aromatic. Arylene groups can be substituted orunsubstituted. In some embodiments, an arylene group may contain 6(i.e., phenylene) ring atoms or be a ring system containing 9 to 15atoms; such as 9 to 11 ring atoms; or 9 or 10 ring atoms. Arylene groupscan be substituted or unsubstituted.

As used herein by themselves or in conjunction with another term orterms, “alkylaryl” and “alkylaryl group” refer to an alkyl group inwhich a hydrogen atom is replaced by an aryl group, wherein alkyl groupand aryl group are as previously defined, such as, for example, benzyl(C₆H₅CH₂—). Alkylaryl groups can be substituted or unsubstituted.

As used herein by themselves or in conjunction with another term orterms, “carbocyclic group” and “carbocycle” refer to monocyclic andpolycyclic ring systems that contain only carbon atoms in the ring(s),i.e., hydrocarbon ring systems, without regard or reference toaromaticity or degree of unsaturation. Thus, carbocyclic group should beunderstood as referring to and including ring systems that are fullysaturated (such as, for example, a cyclohexyl group), ring systems thatare aromatic (such as, for example, a phenyl group), as well as ringsystems having fully saturated, aromatic and/or unsaturated portions(such as, for example, cyclohexenyl, 2,3-dihydro-indenyl, and1,2,3,4-tetrahydro-naphthalenyl). The terms carbocyclic and carbocyclefurther include bridged, fused, and spirocyclic ring systems.

As used herein by themselves or in conjunction with another term orterms, “cycloalkyl” and “cycloalkyl group” refer to a non-aromaticcarbocyclic ring system, that may be monocyclic, bicyclic, or tricyclic,saturated or unsaturated, and may be bridged, spiro, and/or fused. Acycloalkyl group may be substituted or unsubstituted. Unless specifiedotherwise, a cycloalkyl group typically contains from 3 to 12 ringatoms. In some instances a cycloalkyl group may contain 4 to 10 ringatoms (e.g., 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms,etc.). Representative examples include, but are not limited to,cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl,bicyclo[2.2.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene,bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[3.3.2]decane.

As used herein by themselves or in conjunction with another term orterms, “alkylcycloalkyl” and “alkylcycloalkyl group” refer to an alkylgroup in which a hydrogen atom is replaced by a cycloalkyl group,wherein alkyl group and cycloalkyl group are as previously defined, suchas, for example, cyclohexylmethyl (C₆H₁₁CH₂—). Alkylcycloalkyl groupscan be substituted or unsubstituted.

As used herein by themselves or in conjunction with another term orterms, “haloalkyl” and “haloalkyl group” refer to alkyl groups in whichone or more hydrogen atoms are replaced by halogen atoms. Haloalkylincludes both saturated alkyl groups as well as unsaturated alkenyl andalkynyl groups. Representative examples include, but are not limited to,—CF₃, —CHF₂, —CH₂F, —CF₂CF₃, —CHFCF₃, —CH₂CF₃, —CF₂CH₃, —CHFCH₃,—CF₂CF₂CF₃, —CF₂CH₂CH₃, —CF═CF₂, —CCl═CH₂, —CBr═CH₂, —Cl═CH₂, —C≡C—CF₃,—CHFCH₂CH₃ and —CHFCH₂CF₃. Haloalkyl groups can be substituted orunsubstituted.

As used herein by themselves or in conjunction with another term orterms, “halo” and “halogen” include fluorine, chlorine, bromine andiodine atoms and substituents.

As used herein by themselves or in conjunction with another term orterms, “heteroaryl” and “heteroaryl group” refer to (a) 5 and 6 memberedmonocyclic aromatic rings, which contain, in addition to carbon atom(s),at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 7to 15 membered bicyclic and tricyclic rings, which contain, in additionto carbon atom(s), at least one heteroatom, such as nitrogen, oxygen orsulfur, and in which at least one of the rings is aromatic. In someinstances, a heteroaryl group can contain two or more heteroatoms, whichmay be the same or different. Heteroaryl groups can be substituted orunsubstituted, and may be bridged, spiro, and/or fused. In someinstances, a heteroaryl group may contain 5, 6, or 8 to 15 ring atoms.In other instances, a heteroaryl group may contain 5 to 10 ring atoms,such as 5, 6, 9, or 10 ring atoms. Representative examples include, butare not limited to, 2,3-dihydrobenzofuranyl, 1,2-dihydroquinolinyl,3,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl,furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl,2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl,pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, thienyl,2-thienyl, 3-thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl,triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl,pyrazin-2-yl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl,alloxazinyl, benzimidazolyl, benzofuranyl, benzofurazanyl,2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl,benzothiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl,indolizinyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H-indolyl,quinazolinyl, quinoxalinyl, isoindolyl, isoquinolinyl,10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienyl,12-oxa-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienyl,12-aza-tricyclo[7.2.1.0^(2,7)]dodeca-2(7),3,5-trienyl,10-aza-tricyclo[6.3.2.0^(2,7)]trideca-2(7),3,5-trienyl,2,3,4,5-tetrahydro-1H-benzo[d]azepinyl,1,3,4,5-tetrahydro-benzo[d]azepin-2-onyl,1,3,4,5-tetrahydro-benzo[b]azepin-2-onyl,2,3,4,5-tetrahydro-benzo[c]azepin-1-onyl,1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-onyl,2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl,5,6,8,9-tetrahydro-7-oxa-benzocycloheptenyl,2,3,4,5-tetrahydro-1H-benzo[b]azepinyl,1,2,4,5-tetrahydro-benzo[e][1,3]diazepin-3-onyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-onyl,6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl,5,5-dioxo-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, and2,3,4,5-tetrahydro-benzo[f][1,4]oxazepinyl. Suitably, a heteroaryl is a5- or 6-membered heteroaryl ring comprising one, two or threeheteroatoms selected from N, O or S.

As used herein by themselves or in conjunction with another term orterms, “alkylheteroaryl” and “alkylheteroaryl group” refer to an alkylgroup in which a hydrogen atom is replaced by a heteroaryl group,wherein alkyl group and heteroaryl group are as previously defined.Alkylheteroaryl groups can be substituted or unsubstituted.

As used herein by themselves or in conjunction with another term orterms, “heterocyclic group” and “heterocycle” refer to monocyclic andpolycyclic ring systems that contain carbon atoms and at least oneheteroatom selected from nitrogen, oxygen, sulfur or phosphorus in thering(s), without regard or reference to aromaticity or degree ofunsaturation. Thus, a heterocyclic group should be understood asreferring to and including ring systems that are fully saturated (suchas, for example, a piperidinyl group), ring systems that are aromatic(such as, for example, a pyrindinyl group), as well as ring systemshaving fully saturated, aromatic and/or unsaturated portions (such as,for example, 1,2,3,6-tetrahydropyridinyl and6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrizinyl). The terms heterocyclicand heterocycle further include bridged, fused, and spirocyclic ringsystems.

As used herein by themselves or in conjunction with another term orterms, “heterocycloalkyl” and “heterocycloalkyl group” refer to 3 to15membered monocyclic, bicyclic, and tricyclic non-aromatic ring systems,which contain, in addition to carbon atom(s), at least one heteroatom,such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkyl groupsmay be fully saturated or contain unsaturated portions and may bebridged, spiro, and/or fused ring systems. In some instances aheterocycloalkyl group may contain at least two or heteroatoms, whichmay be the same or different. Heterocycloalkyl groups can be substitutedor unsubstituted. In some instances a heterocycloalkyl group may containfrom 3 to 10 ring atoms or from 3 to 7 ring atoms or from 5 to 7 ringatoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms.Representative examples include, but are not limited to,tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl,indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl,homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide,thiomorpholinyl-S,S-dioxide, pyrrolidinyl, tetrahydropyranyl,piperidinyl, tetrahydrothienyl, homopiperidinyl,homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl,dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,dihydrofuryl, dihydropyranyl, tetrahydrothienyl-5-oxide,tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-5-oxide,quinuclidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl,8-oxa-3-aza-bicyclo[3.2.1]octanyl, 3,8-diaza-bicyclo[3.2.1]octanyl,2,5-diaza-bicyclo[2.2.1]heptanyl, 3,8-diaza-bicyclo[3.2.1]octanyl,3,9-diaza-bicyclo[4.2.1]nonanyl, 2,6-diaza-bicyclo[3.2.2]nonanyl,[1,4]oxaphosphinanyl-4-oxide, [1,4]azaphosphinanyl-4-oxide,[1,2]oxaphospholanyl-2-oxide, phosphinanyl-1-oxide,[1,3]azaphospholidinynl-3-oxide, [1,3]oxaphospholanyl-3-oxide,7-oxabicyclo[2.2.1]heptanyl,6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl,6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl,6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl,5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]diazepin-7-yl and6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl. Suitably, aheterocyclylalkyl group as defined herein is a monocyclic, bicyclic orspiro heterocyclyl group comprising one, two or three heteroatomsselected from N, O or S.

As used herein by themselves or in conjunction with another term orterms, “heterocycloalkylene” and “heterocycloalkylene group” refer to 3to15 membered monocyclic, bicyclic, or tricyclic non-aromatic ringsystems, which contain, in addition to carbon atom(s), at least oneheteroatom, such as nitrogen, oxygen, sulfur or phosphorus.Heterocycloalkylene groups may be fully saturated or contain unsaturatedportions and may be bridged, spiro, and/or fused. Heterocycloalkylenegroups can be substituted or unsubstituted. In some instances, aheterocycloalkylene group may contain from 3 to 10 ring atoms; such asfrom 3 to 7 ring atoms. In other instances a heterocycloalkylene groupmay contain from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms,or 7 ring atoms.

As used herein by themselves or in conjunction with another term orterms, “alkylheterocycloalkyl” and “alkylheterocycloalkyl group” referto an alkyl group in which a hydrogen atom is replaced by aheterocycloalkyl group, wherein alkyl group and heterocycloalkyl groupare as previously defined, such as, for example, pyrrolidinylmethyl(C₄H₈NCH₂—). Alkylheteroycloalkyl groups can be substituted orunsubstituted.

As used herein by itself or in conjunction with another term or terms,“pharmaceutically acceptable” refers to materials that are generallychemically and/or physically compatible with other ingredients (such as,for example, with reference to a formulation), and/or is generallyphysiologically compatible with the recipient (such as, for example, asubject) thereof.

As used herein by itself or in conjunction with another term or terms,“pharmaceutical composition” refers to a composition that can be used totreat a disease, condition, or disorder in a subject, including a human.

As used herein by itself or in conjunction with another term or terms,“pseudohalogen” refers to —OCN, —SCN, —CF₃, and —CN.

As used herein by themselves or in conjunction with another term orterms, “stable” and “chemically stable” refer to a compound that issufficiently robust to be isolated from a reaction mixture with a usefuldegree of purity. The present application is directed solely to thepreparation of stable compounds. When lists of alternative substituentsinclude members which, owing to valency requirements, chemicalstability, or other reasons, cannot be used to substitute a particulargroup, the list is intended to be read in context to include thosemembers of the list that are suitable for substituting the particulargroup. For example, when considering the degree of optional substitutionof a particular moiety, it should be understood that the number ofsubstituents does not exceed the valency appropriate for that moiety.For example, if R¹ is a methyl group (—CH₃), it can be optionallysubstituted by 1 to 3 R⁵.

As used herein by themselves or in conjunction with another term orterms, “subject(s)” and “patient(s)”, refer to mammals, includinghumans.

As used herein by itself or in conjunction with another term or terms,“substituted” indicates that a hydrogen atom on a molecule has beenreplaced with a different atom or group of atoms and the atom or groupof atoms replacing the hydrogen atom is a “substituent.” It should beunderstood that the terms “substituent”, “substituents”, “moiety”,“moieties”, “group”, or “groups” refer to substituent(s).

As used herein by themselves or in conjunction with another term orterms, “therapeutic” and “therapeutically effective amount” refer to anamount a compound, composition or medicament that (a) inhibits or causesan improvement in a particular disease, condition or disorder; (b)attenuates, ameliorates or eliminates one or more symptoms of aparticular disease, condition or disorder; (c) or delays the onset ofone or more symptoms of a particular disease, condition or disorderdescribed herein. It should be understood that the terms “therapeutic”and “therapeutically effective” encompass any one of the aforementionedeffects (a)-(c), either alone or in combination with any of the others(a)-(c). It should be understood that in, for example, a human or othermammal, a therapeutically effective amount can be determinedexperimentally in a laboratory or clinical setting, or a therapeuticallyeffective amount may be the amount required by the guidelines of theUnited States Food and Drug Administration (FDA) or equivalent foreignregulatory body, for the particular disease and subject being treated.It should be appreciated that determination of proper dosage forms,dosage amounts, and routes of administration is within the level ofordinary skill in the pharmaceutical and medical arts.

As used herein whether by themselves or in conjunction with another termor terms, “treating”, “treated” and “treatment”, refer to and includeprophylactic, ameliorative, palliative, and curative uses and results.In some embodiments, the terms “treating”, “treated”, and “treatment”refer to curative uses and results as well as uses and results thatdiminish or reduce the severity of a particular condition,characteristic, symptom, disorder, or disease described herein. Forexample, treatment can include diminishment of several symptoms of acondition or disorder or complete eradication of said condition ordisorder. It should be understood that the term “prophylactic” as usedherein is not absolute but rather refers to uses and results where theadministration of a compound or composition diminishes the likelihood orseriousness of a condition, symptom, or disease state, and/or delays theonset of a condition, symptom, or disease state for a period of time.

As used herein, a “therapeutically active agent”, whether used alone orin conjunction with another term or terms, refers to any compound, i.e.a drug, that has been found to be useful in the treatment of a disease,disorder or condition and is not described by Formula I. It should beunderstood that a therapeutically active agent may not be approved bythe FDA or an equivalent foreign regulatory body.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a subject or patient for treating a disease,is sufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the subjector patient to be treated.

Compounds

In a first aspect, the present invention relates to a compound ofFormula I:

or a salt or solvate thereof wherein,X is chosen from halogen, haloC₁-C₆alkyl, NO₂, OCN, SCN, —C(═O)NR⁵R⁶,—NHS(O)₂R⁶, and CN;R² is a group A-B-C wherein,

A is a bond or is C₁-C₁₀alkyl;

B is absent or is chosen from S(O)_(p), NR³, O, C₂-C₁₀alkenyl, andC₂-C₁₀alkynyl; and

C is a 3 to 15 membered heterocycloalkyl group or a 4 to 11 memberedcycloalkyl group either of which is optionally substituted with one ormore R⁵ groups; or

R¹ is a heteroaryl group of Formula A

whereinZ¹ is selected from C and N,Z² is selected from CR^(a), NR^(b), N, O and S,Z³ is selected is N and NR^(c),Z⁴ and Z⁵ are independently selected from O, N, S, NR^(d) and CR^(e).R^(a) is selected from hydrogen, hydroxyl, halogen, COOR³, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl,C₀-C₆alkylheterocycloalkyl, C₀-C₆alkylheteroaryl, C₀-C₆alkylCN,C₀-C₆alkylC(═O)C₀-C₆alkylR³, C₀-C₆alkylC(═O)C₀-C₆alkylOR³,C₀-C₆alkylC(═O)C₀-C₆alkylNR³R⁴, haloC₁-C₆alkyl, NO₂, C₀-C₆alkylNR³R⁴,C₀-C₆alkylNR³C₀-C₆alkylOR⁴, C₀-C₆alkylOS(═O)R⁴, —C₀-C₆alkylOS(═O)₂R⁴,—C₀-C₆alkylS(═O)_(p)R⁴, —OCN, and —SCN, wherein any of the foregoing isoptionally substituted with one or more R⁵ groups;R^(b) and R^(c) are independently selected from hydrogen, C₁-C₆ alkyland C₃-C₆ cycloalkyl;R^(a) and R^(c) are taken together to form a fused 6-membered ringoptionally substituted with one or more R⁵ groups;R^(d) is selected from hydrogen, C₁-C₆ alkyl and C₃-C₆ cycloalkyl; andR^(e) is selected from hydrogen, hydroxyl, halogen, OR³, COOR³,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₀-C₆alkylaryl,C₀-C₆alkylcycloalkyl, C₀-C₆alkylheterocycloalkyl, C₀-C₆alkylheteroaryl,C₀-C₆alkylCN, C₀-C₆alkylC(═O)C₀-C₆alkylR³, C₀-C₆alkylC(═O)C₀-C₆alkylOR³,C₀-C₆alkylC(═O)C₀-C₆alkylNR³R⁴, haloC₁-C₆alkyl, NO₂, C₀-C₆alkylNR³R⁴,C₀-C₆alkylNR³C₀-C₆alkylOR⁴, C₀-C₆alkylOS(═O)R⁴, —C₀-C₆alkylOS(═O)₂R⁴,—C₀-C₆alkylS(═O)_(p)R⁴, —OCN, and —SCN; ortwo adjacent R^(e) groups, adjacent R^(c) and R^(e) or adjacent R^(e)and R^(d) groups are taken together to form a fused 6-membered ringoptionally substituted with one or more R⁵ groups;each R³ and R⁴ are each independently chosen from H, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, haloC₁-C₆alkyl, C₀-C₆alkylaryl,C₀-C₆alkylcycloalkyl, C₀-C₆alkylheteroaryl, C₀-C₆alkylheterocycloalkyl,wherein any of the foregoing, except for H, is optionally substitutedwith one or more R⁵; orR³ and R⁴ are taken together to form a 3 to 7 membered carbocyclic orheterocyclic ring system, wherein said ring system is optionallysubstituted with one or more R⁵;Each R⁵ is independently chosen from halogen, hydroxyl, OR⁶,C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, C₀-C₆alkylaryl,C₀-C₆alkylcycloalkyl, C₀-C₆alkylheterocycloalkyl, C₀-C₆alkylheteroaryl,—C₀-C₆alkylCN, —C₀-C₆alkylC(═O)C₀-C₆alkylR⁶,—C₀-C₆alkylC(═O)C₀-C₆alkylOR⁶, —C₀-C₆alkylC(═O)C₀-C₆alkylNR⁶R⁶,—C₀-C₆alkylC(═O)C₀-C₆alkylNR⁶C(═O)OR⁶, haloC₁-C₆alkyl, NO₂,—C₀-C₆alkylNR⁶R⁶, —C₀-C₆alkylNR⁶C₀-C₆alkylOR⁶,—C₀-C₆alkylNR⁶C₀-C₆alkylC(═O)R⁶, —C₀-C₆alkylOR⁶, (═O),—C₀-C₆alkylOC(═O)C₀-C₆alkylR⁶, —C₀-C₆alkylOC(═O)C₀-C₆alkylNR⁶R⁶,—C₀-C₆alkylOC(═O)C₀-C₆alkylOR⁶, —C₀-C₆alkylOS(═O) R⁶,—C₀-C₆alkylOS(═O)₂R⁶, —C₀-C₆alkylOS(═O)₂C₀-C₆alkylOR⁶,—C₀-C₆alkylOS(═O)₂C₀-C₆alkylNR⁶R⁶, —C₀-C₆alkylS(═O)_(p)R⁶,—C₀-C₆alkylS(═O)₂C₀-C₆alkylNR⁶R⁶, —C₀-C₆alkylS(═O)C₀-C₆alkylNR⁶R⁶,wherein each of the foregoing is optionally substituted with R⁷, ortogether with carbon atoms to which they are attached, two R⁵ groups arelinked to form a fused aryl, heteroaryl, 3 to 6 memberedheterocycloalkyl or a 3 to 6 membered cycloalkyl;each R⁶ is independently chosen from H, C₁-C₁₀alkyl, C₂-C₁₀alkenyl,C₂-C₁₀alkynyl, haloC₁-C₆alkyl, C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl,C₀-C₆alkylheteroaryl, C₀-C₆alkylheterocycloalkyl, wherein each of theforegoing is optionally substituted with R⁷; ortwo R⁶ are taken together to form a 3 to 15 membered carbocyclic orheterocyclic ring system, wherein said ring system is optionallysubstituted with one or more R⁷;each R⁷ is independently chosen from halogen, hydroxyl, C₁-C₆alkyl,OC₁-C₆alkyl, and haloC₁-C₆alkyl; andeach p is independently 0, 1 or 2;with the proviso that the compound of Formula I is not one of thefollowing compounds:

-   6-cyclopentyl-5-iodo-2-(5-thiazolyl)-4(3H)-pyrimidinone;-   6-cyclopentyl-2-(1-ethyl-1H-pyrazol-4-yl)-5-iodo-4(3H)-pyrimidinone;-   6-cyclopentyl-5-iodo-2-(1-propyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(1-ethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(1-propyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(1-isopropyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-5-iodo-2(1-isopropyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(5-thiazolyl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(3,5-dimethyl-4-isoxazolyl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(1-propyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-5-iodo-2-(1-methyl-1H-pyrazol-3-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(1-cyclopropyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(1-methyl-1H-pyrazol-3-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(1,5-dimethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-5-iodo-2(1,3,5-trimethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-5-iodo-2-[1    (1-methylethyl)-1H-imidazol-5-yl]-4(3H)-pyrimidinone;-   6-cyclopentyl-5-iodo-2-(1-propyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-2-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(1-methyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(1-methyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-5-iodo-2-(1-methyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2-(1,3-dimethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-2-(1,3-dimethyl-1H-pyrazol-4-yl)-5-iodo-4(3H)-pyrimidinone;-   6-cyclopentyl-2-(3,5-dimethyl-4-isoxazolyl)-5-iodo-4(3H)-pyrimidinone;-   6-cyclopentyl-5-iodo-2-(1-methyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2-[1    (1-methylethyl)-1H-imidazol-5-yl]-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-iodo-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2-(1-ethyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-2-(1-cyclopropyl-1H-imidazol-5-yl)-5-iodo-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2-(1H-1,2,4-triazol-5-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-2-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-5-iodo-4(3H)-pyrimidinone;-   6-cyclopentyl-5-iodo-2-(1H-1,2,3-triazol-5-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-5-iodo-2-(1H-1,2,4-triazol-5-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(1H-1,2,3-triazol-5-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-5-iodo-2-(1-propyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(1-propyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2(1-methyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;-   6-cyclopentyl-5-iodo-2-(1-methyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;-   5-bromo-6-cyclopentyl-2-(1-ethyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;    and-   6-cyclopentyl-2-(1-ethyl-1H-pyrazol-5-yl)-5-iodo-4(3H)-pyrimidinone.

Particular embodiments of the invention include, for example, compoundsof the formula I, or salts and/or solvates thereof, wherein alternativedefinitions of each of p, R₁, R₂, R₃, R₄, R₅, R₆, R₇ and X are definedin the following numbered paragraphs. Where not described otherwise,substituents have the same meaning as described in the first aspectabove.

-   1) Each p is independently 1 or 2;-   2) p is 2;-   3) X is chosen from halogen, haloC₁-C₆alkyl, OCN, SCN, NO₂ and CN;-   4) X is chosen from halogen, haloC₁-C₂alkyl, and CN;-   5) X is chosen from halogen, CF₃, and CN;-   6) X is chosen from fluoro, chloro, bromo, iodo and CN.-   7) X is a halogen;-   8) X is chosen from fluoro or chloro;-   9) X is chloro;-   10) R² is a group A-B-C wherein A is a bond;-   11) R² is a group A-B-C wherein B is absent.-   12) R² is a group A-B-C wherein B is selected from S(O)_(p), NR³ or    O.-   13) R² is a group A-B-C wherein C is a 3 to 7 membered    heterocycloalkyl or a 4 to 7 membered cycloalkyl either of which is    optionally substituted with one or more R⁵.-   14) R² is a group A-B-C wherein C is selected from a 5 to 7 membered    heterocycloalkyl which is optionally substituted with one of more R⁵    group.-   15) R² is a group A-B-C wherein C is selected from:

each optionally substituted with one of more R⁵ group.

-   16) R² is a group A-B-C wherein:    -   A is a bond or is C₁-C₂alkyl;    -   B is absent or is chosen from S, NR³ or 0; and    -   C is a 3 to 12 membered heterocycloalkyl or a 6 to 11 membered        cycloalkyl either of which is optionally substituted with one or        more R⁵;-   17) R² is a group A-B-C wherein:    -   A is a bond;    -   B is absent; and    -   C is a 3 to 7 membered heterocycloalkyl or a 4 to 8 membered        cycloalkyl either of which is optionally substituted with one or        more R⁵ group.-   18) R² is a 3 to 12 membered heterocycloalkyl or a 6 to 11 membered    cycloalkyl either of which is optionally substituted with one or    more R⁵;-   19) R² is a 3 to 12 membered heterocycloalkyl optionally substituted    with one or more R⁵;-   20) R² is a 3 to 8 membered heterocycloalkyl optionally substituted    with one or more R⁵-   21) R² is a 4 to 8 membered heterocycloalkyl optionally substituted    with one or more R⁵-   22) R² is a 5 to 8 membered heterocycloalkyl optionally substituted    with one or more R⁵;-   23) R² is a 6 to 8 membered heterocycloalkyl optionally substituted    with one or more R⁵;-   24) R² is a 6 and 7 membered heterocycloalkyl optionally substituted    with one or more R⁵;-   25) R² is selected from a piperidinyl, piperazinyl, homopiperazinyl,    morpholino and a tetrahydropyranyl group, each of which is    optionally substituted by one or more R⁵ group.-   26) R² is selected from:

each optionally substituted with one of more R⁵ group.

-   27) R² is selected from piperazinyl, homopiperazinyl and morpholino,    each of which is optionally substituted by one or more R⁵ group.-   28) R² is selected from

each optionally substituted with one of more R⁵ group.

-   29) R² is selected from

-   30) Z¹ is C.-   31) Z² is CR^(a).-   32) Z³ is N.-   33) Z⁵ is O or S-   34) Z⁴ is NR^(b) or N-   35) Z³ is N and Z⁴ is NR^(b).-   36) Z³ is N, Z⁴ is NR^(b) and Z² is CR^(a).-   37) Z³ is N, Z⁴ is NR^(b) and Z⁵ is CR^(e).-   38) Z³ is N, Z⁴ is NH and Z² is CR^(a).-   39) Z³ is N, Z⁴ is NH and Z⁵ is CR^(e).-   40) Z¹ is C, Z³ is N, Z⁴ is NR^(b) and Z² is CR^(a).-   41) Z¹ is C, Z³ is N, Z⁴ is NR^(b), and Z⁵ is CR^(e).-   42) Z³ is N and Z⁵ is S or O.-   43) Z³ is N, Z⁵ is S or O and Z² is CR^(a).-   44) Z³ is N, Z⁵ is S or O, Z¹ is C and Z² is CR^(a).-   45) R¹ is a heteroaryl group of Formula A1:

-   46) R¹ is a heteroaryl group of Formula A2:

-   47) R¹ is a heteroaryl group of Formula A3:

-   48) R¹ is selected from:

-   49) R¹ is selected from

-   50) R¹ is selected from

-   51) R¹ is selected from

-   52) R¹ is selected from

-   53) R³ and R⁴ are each independently chosen from H, C₁-C₃alkyl,    haloC₁-C₃alkyl, C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl,    C₀-C₆alkylheteroaryl, or C₀-C₆alkylheterocycloalkyl;-   54) R³ and R⁴ are each independently chosen from H, C₁-C₃alkyl,    haloC₁-C₃alkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl;-   55) R³ and R⁴ are each independently chosen from H, C₁-C₃alkyl or    haloC₁-C₃alkyl;-   56) R³ and R⁴ are each independently chosen from H, or C₁-C₃alkyl;-   57) Each R⁵ is halogen, hydroxyl, OR⁶, C₁-C₁₀alkyl, C₂-C₁₀alkenyl,    C₂-C₁₀alkynyl, C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl,    C₀-C₆alkylheterocycloalkyl, C₀-C₆alkylheteroaryl, —C₀-C₆alkylCN,    —C₀-C₆alkylC(═O)C₀-C₆alkylR⁶, —C₀-C₆alkylC(═O)C₀-C₆alkylOR⁶,    —C₀-C₆alkylC(═O)C₀-C₆alkylNR⁶R⁶,    —C₀-C₆alkylC(═O)C₀-C₆alkylNR⁶C(═O)OR⁶, haloC₁-C₆alkyl and NO₂,    wherein each of the foregoing is optionally substituted with R⁷, or    together with carbon atoms to which they are attached, two R⁵ groups    are linked to form a fused aryl, heteroaryl, 3 to 6 membered    heterocycloalkyl or a 3 to 6 membered cycloalkyl;-   58) Each R⁵ is halogen, hydroxyl, OR⁶, C₁-C₁₀alkyl, C₂-C₁₀alkenyl,    C₂-C₁₀alkynyl, C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl,    C₀-C₆alkylheterocycloalkyl, C₀-C₆alkylheteroaryl, —C₀-C₆alkylCN,    haloC₁-C₆alkyl and NO₂, wherein each of the foregoing is optionally    substituted with R⁷, or    together with carbon atoms to which they are attached, two R⁵ groups    are linked to form a fused aryl, heteroaryl, 3 to 6 membered    heterocycloalkyl or a 3 to 6 membered cycloalkyl;-   59) Each R⁵ is halogen, hydroxyl, OR⁶, C₁-C₁₀alkyl, C₀-C₆alkylaryl,    C₀-C₆alkylcycloalkyl, C₀-C₆alkylheterocycloalkyl,    C₀-C₆alkylheteroaryl, —C₀-C₆alkylCN, haloC₁-C₆alkyl and NO₂, wherein    each of the foregoing is optionally substituted with R⁷, or    together with carbon atoms to which they are attached, two R⁵ groups    are linked to form a fused aryl, heteroaryl, 3 to 6 membered    heterocycloalkyl or a 3 to 6 membered cycloalkyl;-   60) Each R⁵ is halogen, hydroxyl, OR⁶, C₁-C₆alkyl, C₀-C₆alkylaryl,    C₀-C₆alkylcycloalkyl, C₀-C₆alkylheterocycloalkyl,    C₀-C₆alkylheteroaryl, —C₀-C₆alkylCN, haloC₁-C₆alkyl and NO₂, wherein    each of the foregoing is optionally substituted with R⁷.-   61) Each R⁵ is selected from halogen, hydroxyl, OR⁶, C₁-C₁₀alkyl,    —C₀-C₆alkylC(═O)C₀-C₆alkylR⁶, —C₀-C₆alkylC(═O)C₀-C₆alkylOR⁶,    haloC₁-C₆alkyl, —C₀-C₆alkylOR⁶ and (═O), wherein each of the    foregoing is optionally substituted with R⁷.-   62) Each R⁵ is selected from halogen, hydroxyl, C₁-C₃alkyl,    haloC₁-C₆alkyl and (═O).-   63) Each R⁵ is selected from C₁-C₄alkyl, haloC₁-C₃alkyl or halogen;-   64) Each R⁵ is selected from fluoro, chloro, methyl, trifluoromethyl    and difluoromethyl.-   65) Each R⁶ is independently chosen from H, C₁-C₁₀alkyl,    haloC₁-C₆alkyl, C₀-C₂alkylaryl, C₀-C₂alkylcycloalkyl,    C₀-C₂alkylheteroaryl, C₀-C₂alkylheterocycloalkyl, wherein any of the    foregoing except for H is optionally substituted with one or more    R⁷; or    Two R⁶ may be taken together to form a 3 to 6 membered carbocyclic    or heterocyclic ring system, wherein said ring system is optionally    substituted with one or more R⁷;-   66) Each R⁶ is independently chosen from H, C₁-C₆alkyl,    haloC₁-C₄alkyl, C₀-C₂alkylaryl, C₀-C₂alkyl-5- or 6-membered    cycloalkyl, C₀-C₂alkyl-5- or 6-membered heteroaryl, C₀-C₂alkyl-5- or    6-membered heterocycloalkyl, wherein any of the foregoing except for    H is optionally substituted with one or more R⁷;-   67) Each R⁶ is independently chosen from H, C₁-C₄alkyl,    haloC₁-C₂alkyl, C₀-C₂alkylaryl, C₀-C₂alkyl-5- or 6-membered    cycloalkyl, C₀-C₂alkyl-5- or 6-membered heteroaryl, C₀-C₂alkyl-5- or    6-membered heterocycloalkyl, wherein any of the foregoing except for    H is optionally substituted with one or more R⁷;-   68) Each R⁶ is independently chosen from halogen and C₁-C₄alkyl.-   69) Each R⁷ is independently chosen from halogen, hydroxyl and    C₁-C₆alkyl.-   70) Each R⁷ is independently chosen from halogen and C₁-C₄alkyl.

In one embodiment, X is as defined in any one of paragraphs (5), R¹ isas defined in any one of paragraphs (45) to (52).

In one embodiment, X is as defined in any one of paragraphs (7), R¹ isas defined in any one of paragraphs (45) to (52).

In one embodiment, X is as defined in any one of paragraphs (9), R¹ isas defined in any one of paragraphs (45) to (52).

In one embodiment, X is as defined in any one of paragraphs (5), R¹ isas defined in any one of paragraphs (45) to (52) and R² is as defined inparagraph (24).

In one embodiment, X is as defined in any one of paragraphs (7), R¹ isas defined in any one of paragraphs (45) to (52) and R² is as defined inparagraph (24).

In one embodiment, X is as defined in any one of paragraphs (9), R¹ isas defined in any one of paragraphs (45) to (52) and R² is as defined inparagraph (24).

In one embodiment, X is as defined in any one of paragraphs (5), R¹ isas defined in any one of paragraphs (45) to (52) and R² is as defined inparagraph (26).

In one embodiment, X is as defined in any one of paragraphs (7), R¹ isas defined in any one of paragraphs (45) to (52) and R² is as defined inparagraph (26).

In one embodiment, X is as defined in any one of paragraphs (9), R¹ isas defined in any one of paragraphs (45) to (52) and R² is as defined inparagraph (26).

In one embodiment, X is as defined in any one of paragraphs (5), R¹ isas defined in any one of paragraphs (45) to (52) and R² is as defined inparagraph (28).

In one embodiment, X is as defined in any one of paragraphs (7), R¹ isas defined in any one of paragraphs (45) to (52) and R² is as defined inparagraph (28).

In one embodiment, X is as defined in any one of paragraphs (9), R¹ isas defined in any one of paragraphs (45) to (52) and R² is as defined inparagraph (28).

In one embodiment, X is as defined in any one of paragraphs (5), R² isas defined in any one of paragraphs (10) to (29).

In one embodiment, X is as defined in any one of paragraphs (7), R² isas defined in any one of paragraphs (10) to (29).

In one embodiment, X is as defined in any one of paragraphs (9), R² isas defined in any one of paragraphs (10) to (29).

In one embodiment, X is as defined in any one of paragraphs (5), R² isas defined in any one of paragraphs (10) to (29) and R¹ is as defined inany one of paragraphs (46) and (47).

In one embodiment, X is as defined in any one of paragraphs (7), R² isas defined in any one of paragraphs (10) to (29) and R¹ is as defined inany one of paragraphs (46) and (47).

In one embodiment, X is as defined in any one of paragraphs (9), R² isas defined in any one of paragraphs (10) to (29) and R¹ is as defined inany one of paragraphs (46) and (47).

In one embodiment, X is as defined in any one of paragraphs (5), R² isas defined in any one of paragraphs (10) to (29) and R¹ is as defined inparagraph (48).

In one embodiment, X is as defined in any one of paragraphs (7), R² isas defined in any one of paragraphs (10) to (29) and R¹ is as defined inparagraph (48).

In one embodiment, X is as defined in any one of paragraphs (9), R² isas defined in any one of paragraphs (10) to (29) and R¹ is as defined inparagraph (48).

In one embodiment, X is as defined in any one of paragraphs (5), R² isas defined in any one of paragraphs (10) to (29) and R¹ is as defined inparagraph (52).

In one embodiment, X is as defined in any one of paragraphs (7), R² isas defined in any one of paragraphs (10) to (29) and R¹ is as defined inparagraph (52).

In one embodiment, X is as defined in any one of paragraphs (9), R² isas defined in any one of paragraphs (10) to (29) and R¹ is as defined inparagraph (52).

In one embodiment, the compound of the present invention is according toany one of paragraphs (31), (36), (38), (40), (43) to (49) wherein R^(a)is selected from hydrogen, hydroxyl, halogen, COOR³, C₁-C₆alkyl,C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl, C₀-C₆alkylheterocycloalkyl,C₀-C₆alkylheteroaryl, C₀-C₆alkylCN, haloC₁-C₆alkyl, NO₂,C₀-C₆alkylNR³R⁴, —OCN, and —SCN, wherein any of the foregoing isoptionally substituted with one or more R⁵ groups.

In one embodiment, the compound of the present invention is according toany one of paragraphs (31), (36), (38), (40), (43) to (49) wherein R^(a)is selected from hydrogen, hydroxyl, halogen, C₁-C₃alkyl, —OCN, —SCN,—CN and haloC₁-C₃alkyl.

In one embodiment, the compound of the present invention is according toany one of paragraphs (31), (36), (38), (40), (43) to (49) wherein R^(a)is selected from hydrogen, hydroxyl, fluoro, chloro, methyl, ethyl,trifluoromethyl, NO₂, CN, OCN, SCN and difluoromethyl.

In one embodiment, the compound of the present invention is according toany one of paragraphs (31), (36), (38), (40), (43) to (49) wherein R^(a)is selected from hydrogen, hydroxyl, fluoro, chloro, methyl, ethyl,trifluoromethyl, and difluoromethyl.

In one embodiment, the compound of the present invention is according toany one of paragraphs (31), (36), (38), (40), (43) to (49) wherein R^(a)is selected from chloro and methyl.

In one embodiment, the compound of the present invention is according toany one of paragraphs (37), (39), (41), (46) to (49) wherein R^(e) isselected from hydrogen, hydroxyl, halogen, COOR³, C₁-C₆alkyl,C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl, C₀-C₆alkylheterocycloalkyl,C₀-C₆alkylheteroaryl, C₀-C₆alkylCN, haloC₁-C₆alkyl, NO₂,C₀-C₆alkylNR³R⁴, —OCN, and —SCN, wherein any of the foregoing isoptionally substituted with one or more R⁵ groups.

In one embodiment, the compound of the present invention is according toany one of paragraphs (37), (39), (41), (46) to (49) wherein R^(e) isselected from hydrogen, hydroxyl, halogen, C₁-C₃alkyl, —OCN, —SCN, —CNand haloC₁-C₃alkyl.

In one embodiment, the compound of the present invention is according toany one of paragraphs (37), (39), (41), (46) to (49) wherein R^(e) isselected from hydrogen, hydroxyl, fluoro, chloro, methyl, ethyl,trifluoromethyl, NO₂, CN, OCN, SCN and difluoromethyl.

In one embodiment, the compound of the present invention is according toany one of paragraphs (37), (39), (41), (46) to (49) wherein R^(e) isselected from hydrogen, hydroxyl, fluoro, chloro, methyl, ethyl,trifluoromethyl, and difluoromethyl.

In one embodiment, the compound of the present invention is according toany one of paragraphs (37), (39), (41), (46) to (49) wherein R^(e) isselected from chloro and methyl.

In one embodiment, the compound of the present invention is according toany one of paragraphs (34) to (37), (40) and (41) wherein R^(b) isselected from hydrogen or methyl.

In one embodiment, the compound of the invention is according to any oneof paragraphs (13) to (29) and (48) wherein each R⁵ is independentlyselected from halogen, hydroxyl, OR⁶, C₁-C₁₀alkyl, C₂-C₁₀alkenyl,C₂-C₁₀alkynyl, C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl,C₀-C₆alkylheterocycloalkyl, C₀-C₆alkylheteroaryl, —C₀-C₆alkylCN,—C₀-C₆alkylC(═O)C₀-C₆alkylR⁶, —C₀-C₆alkylC(═O)C₀-C₆alkylOR⁶,—C₀-C₆alkylC(═O)C₀-C₆alkylNR⁶R⁶, —C₀-C₆alkylC(═O)C₀-C₆alkylNR⁶C(═O)OR⁶,haloC₁-C₆alkyl and NO₂, wherein each of the foregoing is optionallysubstituted with R⁷, or

together with carbon atoms to which they are attached, two R⁵ groups arelinked to form a fused aryl, heteroaryl, 3 to 6 memberedheterocycloalkyl or a 3 to 6 membered cycloalkyl;

In one embodiment, the compound of the invention is according to any oneof paragraphs (13) to (29) and (48) wherein each R⁵ is halogen,hydroxyl, OR⁶, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl,C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl, C₀-C₆alkylheterocycloalkyl,C₀-C₆alkylheteroaryl, —C₀-C₆alkylCN, haloC₁-C₆alkyl and NO₂, whereineach of the foregoing is optionally substituted with R⁷, or

together with carbon atoms to which they are attached, two R⁵ groups arelinked to form a fused aryl, heteroaryl, 3 to 6 memberedheterocycloalkyl or a 3 to 6 membered cycloalkyl;

In one embodiment, the compound of the invention is according to any oneof paragraphs (13) to (29) and (48) wherein each R⁵ is halogen,hydroxyl, OR⁶, C₁-C₁₀alkyl, C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl,C₀-C₆alkylheterocycloalkyl, C₀-C₆alkylheteroaryl, —C₀-C₆alkylCN,haloC₁-C₆alkyl and NO₂, wherein each of the foregoing is optionallysubstituted with R⁷, or

together with carbon atoms to which they are attached, two R⁵ groups arelinked to form a fused aryl, heteroaryl, 3 to 6 memberedheterocycloalkyl or a 3 to 6 membered cycloalkyl;

In one embodiment, the compound of the invention is according to any oneof paragraphs (13) to (29) and (48) wherein each R⁵ is halogen,hydroxyl, OR⁶, C₁-C₆alkyl, C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl,C₀-C₆alkylheterocycloalkyl, C₀-C₆alkylheteroaryl, —C₀-C₆alkylCN,haloC₁-C₆alkyl and NO₂, wherein each of the foregoing is optionallysubstituted with R⁷.

In one embodiment, the compound of the invention is according to any oneof paragraphs (13) to (29) and (48) wherein each R⁵ is selected fromhalogen, hydroxyl, OR⁶, C₁-C₁₀alkyl, —C₀-C₆alkylC(═O)C₀-C₆alkylR⁶,—C₀-C₆alkylC(═O)C₀-C₆alkylOR⁶, haloC₁-C₆alkyl, —C₀-C₆alkylOR⁶ and (═O),wherein each of the foregoing is optionally substituted with R⁷.

In one embodiment, the compound of the invention is according to any oneof paragraphs (13) to (29) and (48) wherein each R⁵ is selected fromhalogen, hydroxyl, C₁-C₃alkyl, haloC₁-C₆alkyl and (═O).

In one embodiment, the compound of the invention is according to any oneof paragraphs (13) to (29) and (48) wherein each R⁵ is selected fromC₁-C₄alkyl, haloC₁-C₃alkyl or halogen.

In one embodiment, the compound of the invention is according to any oneof paragraphs (13) to (29) and (48) wherein each R⁵ is selected fromfluoro, chloro, methyl, trifluoromethyl and difluoromethyl.

In another embodiment, the present invention relates to a subgenus ofFormula I, Formula Ib:

or a salt or solvate thereof wherein,

X is chosen from halogen, haloC₁-C₆alkyl and CN;

R² is selected from:

each optionally substituted with one of more R⁵ group;R⁵ is selected from halogen, hydroxyl, C₁-C₃alkyl, haloC₁-C₆alkyl and(═O);Z⁵ is selected from O, N and S; andR^(e) and R^(a) are independently selected from hydrogen, hydroxyl,halogen, C₁-C₃alkyl, —OCN, —SCN, —CN and haloC₁-C₃alkyl.

Particular embodiments of the invention include, for example, compoundsof the formula Ib, or salts and/or solvates thereof, wherein alternativedefinitions of each of X, R², R^(a), R^(e) and Z⁵ are defined in thefollowing numbered paragraphs. Where not described otherwise,substituents have the same meaning as described for formula Ib above.

-   1) X is chosen from halogen, haloC₁-C₂alkyl, and CN;-   2) X is chosen from halogen, CF₃, and CN;-   3) X is chosen from fluoro, chloro, bromo, iodo and CN.-   4) X is a halogen;-   5) X is chosen from fluoro or chloro;-   6) X is chloro;-   7) R² is selected from

each optionally substituted with one of more R⁵ group.

-   8) R² is selected from

-   9) Z⁵ is O or S-   10) Z⁵ is S-   11) R^(a) and R^(e) are independently selected from hydrogen,    hydroxyl, fluoro, chloro, methyl, ethyl, trifluoromethyl, and    difluoromethyl.-   12) R^(a) and R^(e) are independently selected from hydrogen, chloro    and methyl.

In one embodiment, the compound of the invention is a compound offormula Ib according to any one of paragraphs (1) to (12) above whereinR^(e) is hydrogen.

In one embodiment, the compound of the invention is a compound offormula Ib according to any one of paragraphs (1) to (12) above whereinR^(a) is selected from chloro and methyl.

In one embodiment, the compound of the invention is a compound offormula Ib according to any one of paragraphs (7) and (8) above whereinR⁵ is selected from fluoro, chloro, methyl, trifluoromethyl anddifluoromethyl.

In another embodiment, the present invention relates to a subgenus ofFormula I, Formula Ic:

or a salt or solvate thereof wherein,

X is chosen from halogen, haloC₁-C₆alkyl and CN;

R² is selected from:

each optionally substituted with one of more R⁵ group;R⁵ is selected from halogen, hydroxyl, C₁-C₃alkyl, haloC₁-C₆alkyl and(═O);Z⁴ is selected from CR^(e), NR^(d), O and S; andR^(e) and R^(a) are independently selected from hydrogen, hydroxyl,halogen, C₁-C₃alkyl, —OCN, —SCN, —CN and haloC₁-C₃alkyl.

Particular embodiments of the invention include, for example, compoundsof the formula Ic, or salts and/or solvates thereof, wherein alternativedefinitions of each of X, R², R^(a), R^(e) and Z⁵ are defined in thefollowing numbered paragraphs. Where not described otherwise,substituents have the same meaning as described for formula Ic above.

-   1) X is chosen from halogen, haloC₁-C₂alkyl, and CN;-   2) X is chosen from halogen, CF₃, and CN;-   3) X is chosen from fluoro, chloro, bromo, iodo and CN.-   4) X is a halogen;-   5) X is chosen from fluoro or chloro;-   6) X is chloro;-   7) R² is selected from

each optionally substituted with one of more R⁵ group.

-   8) R² is selected from

-   9) Z⁴ is O, S or NR^(d)-   10) Z⁴ is NR^(d)-   11) R^(d) is methyl or hydrogen-   12) Z⁴ is NH-   13) R^(a) and R^(e) are independently selected from hydrogen,    hydroxyl, fluoro, chloro, methyl, ethyl, trifluoromethyl, and    difluoromethyl.-   14) R^(a) and R^(e) are independently selected from hydrogen,    chloro, CF₃ and methyl.

In one embodiment, the compound of the invention is a compound offormula Ic according to any one of paragraphs (1) to (14) above whereinR^(e) is methyl, ethyl, CF₃, chloro.

In one embodiment, the compound of the invention is a compound offormula Ic according to any one of paragraphs (1) to (14) above whereinR^(a) is selected from hydrogen, fluoro, chloro, methyl, trifluoromethyland difluoromethyl.

In one embodiment, the compound of the invention is a compound offormula Ic according to any one of paragraphs (1) to (14) above whereinR^(a) is hydrogen and R^(e) is selected from chloro, methyl, ethyl andtrifluoromethyl.

In one embodiment, the compound of the invention is a compound offormula Ic according to any one of paragraphs (7) and (8) above whereinR⁵ is selected from fluoro, chloro, methyl, trifluoromethyl anddifluoromethyl.

In one embodiment, the present invention relates to a compound selectedfrom:

-   tert-butyl    4-[5-chloro-2-(4-methylthiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]piperidine-1-carboxylate;-   5-chloro-2-(4-methylthiazol-5-yl)-4-(4-piperidyl)-1H-pyrimidin-6-one;-   5-chloro-4-[1-(2,2-difluorocyclopropanecarbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[1-(4-methylthiazole-5-carbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(4-methylthiazol-5-yl)-4-[1-(thiazole-4-carbonyl)-4-piperidyl]-1H-pyrimidin-6-one;-   5-chloro-4-[1-(3-methyl-1H-pyrazole-5-carbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[1-(1,5-dimethylpyrazole-3-carbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[1-(2,5-dimethylpyrazole-3-carbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[1-(5-methylisoxazole-3-carbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(4-methylthiazol-5-yl)-4-[1-(pyridazine-4-carbonyl)-4-piperidyl]-1H-pyrimidin-6-one;-   5-chloro-4-(1-isobutyl-4-piperidyl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(4-methylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;-   5-chloro-2-(5-ethyl-1H-pyrazol-4-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;-   5-chloro-4-tetrahydropyran-4-yl-2-thiazol-5-yl-1H-pyrimidin-6-one;-   5-chloro-2-(4-methylthiadiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;-   5-chloro-2-(4-methyloxazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;-   5-fluoro-2-(4-methylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;-   5-bromo-2-(4-methylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;-   5-iodo-2-(4-methylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;-   2-(4-methylthiazol-5-yl)-6-oxo-4-tetrahydropyran-4-yl-1H-pyrimidine-5-carbonitrile;-   5-chloro-2-(2-hydroxy-4-methyl-thiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;-   5-chloro-4-(4-hydroxy-1-piperidyl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-(4-methyl-1-piperidyl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(4-methylthiazol-5-yl)-4-[3-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-4-[(3-methylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[(3R)-3-methylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[4-(hydroxymethyl)-1-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   4-[5-chloro-2-(4-methylthiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-1,4-diazepan-2-one;-   5-chloro-4-(3,3-difluoro-1-piperidyl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[3-(hydroxymethyl)-1-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[(3S)-3-methylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(4-methylthiazol-5-yl)-4-piperazin-1-yl-1H-pyrimidin-6-one;-   5-chloro-2-(4-ethylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;-   5-chloro-2-(3-methyl-1H-pyrazol-4-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;-   5-chloro-2-(4-methylthiazol-5-yl)-4-[3-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-methylthiazol-5-yl)-4-[(3R)-3-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;-   5-chloro-4-tetrahydropyran-4-yl-2-[4-(trifluoromethyl)thiazol-5-yl]-1H-pyrimidin-6-one;-   5-chloro-4-[3-isopropylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[(3S)-3-isopropylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-tetrahydropyran-4-yl-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(2-methylpyrazol-3-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;-   5-chloro-2-(5-methyl-1H-pyrazol-4-yl)-4-morpholino-1H-pyrimidin-6-one;-   5-chloro-4-morpholino-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;-   5-chloro-4-[2-methylpiperazin-1-yl]-2-(5-methyl-1H-pyrazol-4-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[(2R)-2-methylpiperazin-1-yl]-2-(5-methyl-1H-pyrazol-4-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[3-methylmorpholin-4-yl]-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;-   5-chloro-4-[(3R)-3-methylmorpholin-4-yl]-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;-   5-chloro-4-[2-methylpiperazin-1-yl]-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;-   5-chloro-4-[(2R)-2-methylpiperazin-1-yl]-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;-   5-chloro-4-[3-methylmorpholin-4-yl]-2-pyrazolo[1,5-a]pyridin-3-yl-1H-pyrimidin-6-one;-   5-chloro-4-[(3R)-3-methylmorpholin-4-yl]-2-pyrazolo[1,5-a]pyridin-3-yl-1H-pyrimidin-6-one;-   5-chloro-4-[2-methylpiperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[(2R)-2-methylpiperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-6-one;-   5-chloro-4-(6,6-difluoro-1,4-diazepan-1-yl)-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(5-chloro-1H-pyrazol-4-yl)-4-[(2R)-2-methylpiperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-4-(6,6-difluoro-1,4-diazepan-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-6-one;-   5-chloro-4-(2,2-dimethylpiperazin-1-yl)-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;-   5-chloro-4-[2-methylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[(2R)-2-methylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(3-methylisoxazol-4-yl)-4-[(2R)-2-methylpiperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-4-[3-methylmorpholin-4-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[(3R)-3-methylmorpholin-4-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-(6,6-difluoro-1,4-diazepan-1-yl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(5-chloro-1H-pyrazol-4-yl)-4-[3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(5-chloro-1H-pyrazol-4-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-methylthiazol-5-yl)-4-[2-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-4-[2-(difluoromethyl)piperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-4-(6-fluoro-1,4-diazepan-1-yl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-methylpiperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2R)-2-methylpiperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-4-[2-methylpiperazin-1-yl]-2-(2-methylpyrazol-3-yl)-1H-pyrimidin-6-one;-   5-chloro-4-[(2R)-2-methylpiperazin-1-yl]-2-(2-methylpyrazol-3-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-(6,6-difluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(2-methylimidazol-1-yl)-4-[3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(2-methylimidazol-1-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(5-chloro-1H-pyrazol-4-yl)-4-(6,6-difluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-one;-   5-chloro-4-(6,6-difluoro-1,4-diazepan-1-yl)-2-[4-(trifluoromethyl)thiazol-5-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-(6-fluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2S)-2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2R)—R-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[6-fluoro-1,4-diazepan-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[(6S)-6-fluoro-1,4-diazepan-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[(6R)-6-fluoro-1,4-diazepan-1-yl]-1H-pyrimidin-6-one,    or a salt or solvate thereof.

In another embodiment, the present invention relates to a compoundselected from5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-methylpiperazin-1-yl]-1H-pyrimidin-6-one;

-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2R)-2-methylpiperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-(6,6-difluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-(6-fluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2S)-2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2R)—    R-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[6-fluoro-1,4-diazepan-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[(6R)-6-fluoro-1,4-diazepan-1-yl]-1H-pyrimidin-6-one;-   5-chloro-2-(4-chlorothiazol-5-yl)-4-[(6S)-6-fluoro-1,4-diazepan-1-yl]-1H-pyrimidin-6-one,    or a salt or solvate thereof.

Though the present invention may relate to any compound or particulargroup of compounds defined herein by way of optional, preferred orsuitable features or otherwise in terms of particular embodiments, thepresent invention may also relate to any compound or particular group ofcompounds that specifically excludes said optional, preferred orsuitable features or particular embodiments.

Suitably, the present invention excludes any individual compounds notpossessing the biological activity defined herein.

Salts and Solvates

The compounds (including final products and intermediates) describedherein may be isolated and used per se or may be isolated in the form ofa salt, suitably pharmaceutically acceptable salts. It should beunderstood that the terms “salt(s)” and “salt form(s)” used bythemselves or in conjunction with another term or terms encompasses allinorganic and organic salts, including industrially acceptable salts, asdefined herein, and pharmaceutically acceptable salts, as definedherein, unless otherwise specified. As used herein, industriallyacceptable salts are salts that are generally suitable for manufacturingand/or processing (including purification) as well as for shipping andstorage, but may not be salts that are typically administered forclinical or therapeutic use. Industrially acceptable salts may beprepared on a laboratory scale, i.e. multi-gram or smaller, or on alarger scale, i.e. up to and including a kilogram or more.

Pharmaceutically acceptable salts, as used herein, are salts that aregenerally chemically and/or physically compatible with the otheringredients comprising a formulation, and/or are generallyphysiologically compatible with the recipient thereof. Pharmaceuticallyacceptable salts may be prepared on a laboratory scale, i.e. multi-gramor smaller, or on a larger scale, i.e. up to and including a kilogram ormore. It should be understood that pharmaceutically acceptable salts arenot limited to salts that are typically administered or approved by theFDA or equivalent foreign regulatory body for clinical or therapeuticuse in humans. A practitioner of ordinary skill will readily appreciatethat some salts are both industrially acceptable as well aspharmaceutically acceptable salts. It should be understood that all suchsalts, including mixed salt forms, are within the scope of theapplication.

In one embodiment, the compounds of formula are isolated aspharmaceutically acceptable salts.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic,formic, citric or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

In general, salts of the present application can be prepared in situduring the isolation and/or purification of a compound (includingintermediates), or by separately reacting the compound (or intermediate)with a suitable organic or inorganic acid or base (as appropriate) andisolating the salt thus formed. The degree of ionisation in the salt mayvary from completely ionised to almost non-ionised. In practice, thevarious salts may be precipitated (with or without the addition of oneor more co-solvents and/or anti-solvents) and collected by filtration orthe salts may be recovered by evaporation of solvent(s). Salts of thepresent application may also be formed via a “salt switch” or ionexchange/double displacement reaction, i.e. reaction in which one ion isreplaced (wholly or in part) with another ion having the same charge.One skilled in the art will appreciate that the salts may be preparedand/or isolated using a single method or a combination of methods.

Representative salts include, but are not limited to, acetate,aspartate, benzoate, besylate, bicarbonate/carbonate,bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate,formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate, trifluoroacetate and the like. Otherexamples of representative salts include alkali or alkaline earth metalcations such as sodium, lithium, potassium, calcium, magnesium, and thelike, as well as non-toxic ammonium, quaternary ammonium and aminecations including, but not limited to, ammonium, tetramethylammonium,tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine,diolamine, glycine, meglumine, olamine and the like.

Certain compounds of the formula I may exist in solvated as well asunsolvated forms such as, for example, hydrated forms. It is to beunderstood that the invention encompasses all such solvated forms thatpossess antiproliferative activity.

Polymorphs

It is also to be understood that certain compounds of the formula I mayexhibit polymorphism, and that the invention encompasses all such formsthat possess antiproliferative activity.

N-oxides

Compounds of the formula I containing an amine function may also formN-oxides. A reference herein to a compound of the formula I thatcontains an amine function also includes the N-oxide. Where a compoundcontains several amine functions, one or more than one nitrogen atom maybe oxidised to form an N-oxide. Particular examples of N-oxides are theN-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containingheterocycle. N-Oxides can be formed by treatment of the correspondingamine with an oxidizing agent such as hydrogen peroxide or a per-acid(e.g. a peroxycarboxylic acid), see for example Advanced OrganicChemistry, by Jerry March, 4^(th) Edition, Wiley Interscience, pages.More particularly, N-oxides can be made by the procedure of L. W. Deady(Syn. Comm. 1977, 7, 509-514) in which the amine compound is reactedwith m-chloroperoxybenzoic acid (mCPBA), for example, in an inertsolvent such as dichloromethane.

Tautomers

Compounds of the formula I may exist in a number of different tautomericforms and references to compounds of the formula I include all suchforms. For the avoidance of doubt, where a compound can exist in one ofseveral tautomeric forms, and only one is specifically described orshown, all others are nevertheless embraced by formula I. Examples oftautomeric forms include keto-, enol-, and enolate-forms, as in, forexample, the following tautomeric pairs: keto/enol (illustrated below),pyrimidone/hydroxypyrimidine, imine/enamine, amide/imino alcohol,amidine/amidine, nitroso/oxime, thioketone/enethiol, andnitro/aci-nitro.

Isomers

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”.

Certain compounds of Formula I may have one or more asymmetric centersand therefore can exist in a number of stereoisomeric configurations.Consequently, such compounds can be synthesized and/or isolated asmixtures of enantiomers and/or as individual (pure) enantiomers, and, inthe case of two or more asymmetric centers, single diastereomers and/ormixtures of diastereomers. It should be understood that the presentapplication includes all such enantiomers and diastereomers and mixturesthereof in all ratios.

Isotopes

The compounds of the present invention are described herein usingstructural formulas that do not specifically recite the mass numbers orthe isotope ratios of the constituent atoms. As such it is intended thatthe present application includes compounds in which the constituentatoms are present in any ratio of isotope forms. For example, carbonatoms may be present in any ratio of ¹²C, ¹³C, and ¹⁴C; hydrogen atomsmay be present in any ratio of ¹H, ²H, and ³H; etc. Preferably, theconstituent atoms in the compounds of the present invention are presentin their naturally occurring ratios of isotope forms.

Prodrugs and Metabolites

The compounds of formula I may be administered in the form of a pro-drugwhich is broken down in the human or animal body to release a compoundof the invention. A pro-drug may be used to alter the physicalproperties and/or the pharmacokinetic properties of a compound of theinvention. A pro-drug can be formed when the compound of the inventioncontains a suitable group or substituent to which a property-modifyinggroup can be attached. Examples of pro-drugs include in vivo cleavableester derivatives that may be formed at a carboxy group or a hydroxygroup in a compound of the formula I and in-vivo cleavable amidederivatives that may be formed at a carboxy group or an amino group in acompound of the formula I.

Accordingly, the present invention includes those compounds of theformula I as defined hereinbefore when made available by organicsynthesis and when made available within the human or animal body by wayof cleavage of a pro-drug thereof. Accordingly, the present inventionincludes those compounds of the formula I that are produced by organicsynthetic means and also such compounds that are produced in the humanor animal body by way of metabolism of a precursor compound, that is acompound of the formula I may be a synthetically-produced compound or ametabolically-produced compound.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I is one that is based on reasonable medical judgement as beingsuitable for administration to the human or animal body withoutundesirable pharmacological activities and without undue toxicity.

Various forms of pro-drug have been described, for example in thefollowing documents:—

-   a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder,    et al. (Academic Press, 1985);-   b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991);-   d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988);-   f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);-   g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”,    A.C.S. Symposium Series, Volume 14; and-   h) E. Roche (editor), “Bioreversible Carriers in Drug Design”,    Pergamon Press, 1987.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses a carboxy group is, for example, an in vivocleavable ester thereof. An in vivo cleavable ester of a compound of theformula I containing a carboxy group is, for example, a pharmaceuticallyacceptable ester which is cleaved in the human or animal body to producethe parent acid. Suitable pharmaceutically acceptable esters for carboxyinclude C₁₋₆alkyl esters such as methyl, ethyl and tert-butyl,C₁₋₆alkoxymethyl esters such as methoxymethyl esters,C₁₋₆alkanoyloxymethyl esters such as pivaloyloxymethyl esters,3-phthalidyl esters, C₃₋₈cycloalkylcarbonyloxy-C₁₋₆alkyl esters such ascyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,2-oxo-1,3-dioxolenylmethyl esters such as5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters andC₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl esters such as methoxycarbonyloxymethyland 1-methoxycarbonyloxyethyl esters.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses a hydroxy group is, for example, an in vivocleavable ester or ether thereof. An in vivo cleavable ester or ether ofa compound of the formula I containing a hydroxy group is, for example,a pharmaceutically acceptable ester or ether which is cleaved in thehuman or animal body to produce the parent hydroxy compound. Suitablepharmaceutically acceptable ester forming groups for a hydroxy groupinclude inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters). Further suitable pharmaceuticallyacceptable ester forming groups for a hydroxy group includeC₁₋₁₀alkanoyl groups such as acetyl, benzoyl, phenylacetyl andsubstituted benzoyl and phenylacetyl groups, C₁₋₁₀alkoxycarbonyl groupssuch as ethoxycarbonyl, N,N—(C₁₋₆)₂carbamoyl, 2-dialkylaminoacetyl and2-carboxyacetyl groups. Examples of ring substituents on thephenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl,N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and4-(C₁₋₄alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptableether forming groups for a hydroxy group include a-acyloxyalkyl groupssuch as acetoxymethyl and pivaloyloxymethyl groups.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses a carboxy group is, for example, an in vivocleavable amide thereof, for example an amide formed with an amine suchas ammonia, a C₁₋₄alkylamine such as methylamine, a (C₁₋₄alkyl)₂aminesuch as dimethylamine, N-ethyl-N-methylamine or diethylamine, aC₁₋₄alkoxy-C₂₋₄alkylamine such as 2-methoxyethylamine, aphenyl-C₁₋₄alkylamine such as benzylamine and amino acids such asglycine or an ester thereof.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses an amino group is, for example, an in vivocleavable amide derivative thereof. Suitable pharmaceutically acceptableamides from an amino group include, for example an amide formed withC₁₋₄alkanoyl groups such as an acetyl, benzoyl, phenylacetyl andsubstituted benzoyl and phenylacetyl groups. Examples of ringsubstituents on the phenylacetyl and benzoyl groups include aminomethyl,N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl,piperazin-1-ylmethyl and 4-(C₁₋₄alkyl)piperazin-1-ylmethyl.

The in vivo effects of a compound of the formula I may be exerted inpart by one or more metabolites that are formed within the human oranimal body after administration of a compound of the formula I. Asstated hereinbefore, the in vivo effects of a compound of the formula Imay also be exerted by way of metabolism of a precursor compound (apro-drug).

Pharmaceutical Compositions

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt, hydrateor solvate thereof, in association with a pharmaceutically acceptablediluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular,intraperitoneal or intramuscular dosing or as a suppository for rectaldosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

An effective amount of a compound of the present invention for use intherapy is an amount sufficient to treat or prevent a proliferativecondition referred to herein, slow its progression and/or reduce thesymptoms associated with the condition.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the individual treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

It is to be noted that dosages and dosing regimens may vary with thetype and severity of the condition to be alleviated, and may include theadministration of single or multiple doses, i.e. QD (once daily), BID(twice daily), etc., over a particular period of time (days or hours).It is to be further understood that for any particular subject orpatient, specific dosage regimens may need to be adjusted over timeaccording to the individual need and the professional judgment of theperson administering or supervising the administration of thepharmaceutical compositions. For example, doses may be adjusted based onpharmacokinetic or pharmacodynamic parameters, which may includeclinical effects such as toxic effects and/or laboratory values. Thus,the present application encompasses intra-patient dose-escalation asdetermined by the person skilled in the art. Procedures and processesfor determining the appropriate dosage(s) and dosing regimen(s) arewell-known in the relevant art and would readily be ascertained by theskilled artisan. As such, one of ordinary skill would readily appreciateand recognize that the dosage ranges set forth herein are exemplary onlyand are not intended to limit the scope or practice of thepharmaceutical compositions described herein.

In using a compound of the invention for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.1 mg/kg to 75 mg/kg body weight is received, givenif required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous or intraperitoneal administration, a dose in the range, forexample, 0.1 mg/kg to 30 mg/kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.05 mg/kg to 25 mg/kg body weight will be used. Oraladministration may also be suitable, particularly in tablet form.Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of acompound of this invention.

Therapeutic Uses and Applications

The present invention provides compounds that function as inhibitors ofCdc7.

The present invention therefore provides a method of inhibiting Cdc7enzyme activity in vitro or in vivo, said method comprising contacting acell with an effective amount of a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, as defined herein.

The present invention also provides a method of treating a disease ordisorder in which Cdc7 activity is implicated in a patient in need ofsuch treatment, said method comprising administering to said patient atherapeutically effective amount of a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, or a pharmaceuticalcomposition as defined herein.

The present invention provides a method of inhibiting cellproliferation, in vitro or in vivo, said method comprising contacting acell with an effective amount of a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, as defined herein.

The present invention provides a method of treating a proliferativedisorder in a patient in need of such treatment, said method comprisingadministering to said patient a therapeutically effective amount of acompound, or a pharmaceutically acceptable salt, hydrate or solvatethereof, or a pharmaceutical composition as defined herein.

The present invention provides a method of treating cancer in a patientin need of such treatment, said method comprising administering to saidpatient a therapeutically effective amount of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, or apharmaceutical composition as defined herein.

The present invention provides a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, or a pharmaceuticalcomposition as defined herein for use in therapy.

The present invention provides a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, or a pharmaceuticalcomposition as defined herein for use in the treatment of aproliferative condition.

The present invention provides a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, or a pharmaceuticalcomposition as defined herein for use in the treatment of cancer. In aparticular embodiment, the cancer is human cancer.

The present invention provides a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, as defined herein for usein the inhibition of Cdc7 enzyme activity.

The present invention provides a compound, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, as defined herein for usein the treatment of a disease or disorder in which Cdc7 activity isimplicated.

The present invention provides a use of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, as definedherein in the manufacture of a medicament for the treatment of aproliferative condition.

The present invention provides a use of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, as definedherein in the manufacture of a medicament for the treatment of cancer.Suitably, the medicament is for use in the treatment of human cancers.

The present invention provides a use of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, as definedherein in the manufacture of a medicament for the inhibition of Cdc7enzyme activity.

The present invention provides a use of a compound, or apharmaceutically acceptable salt, hydrate or solvate thereof, as definedherein in the manufacture of a medicament for the treatment of a diseaseor disorder in which Cdc7 activity is implicated.

The term “proliferative disorder” are used interchangeably herein andpertain to an unwanted or uncontrolled cellular proliferation ofexcessive or abnormal cells which is undesired, such as, neoplastic orhyperplastic growth, whether in vitro or in vivo. Examples ofproliferative conditions include, but are not limited to, pre-malignantand malignant cellular proliferation, including but not limited to,malignant neoplasms and tumours, cancers, leukemias, psoriasis, bonediseases, fibroproliferative disorders (e.g., of connective tissues),and atherosclerosis. Any type of cell may be treated, including but notlimited to, lung, colon, breast, ovarian, prostate, liver, pancreas,brain, and skin.

The anti-proliferative effects of the compounds of the present inventionhave particular application in the treatment of human cancers (by virtueof their inhibition of Cdc7 enzyme activity).

The anti-cancer effect may arise through one or more mechanisms,including but not limited to, the regulation of cell proliferation, theinhibition of angiogenesis (the formation of new blood vessels), theinhibition of metastasis (the spread of a tumour from its origin), theinhibition of invasion (the spread of tumour cells into neighbouringnormal structures), or the promotion of apoptosis (programmed celldeath).

In a particular embodiment of the invention, the proliferative conditionto be treated is cancer. For example, lung cancer, colon cancer, breastcancer, ovarian cancer, prostate cancer, liver cancer, pancreaticcancer, brain cancer and skin cancer.

Routes of Administration

The compounds of the invention or pharmaceutical compositions comprisingthese compounds may be administered to a subject by any convenient routeof administration, whether systemically/peripherally or topically (i.e.,at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g., byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intra-arterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

Combination Therapies

The antiproliferative treatment defined hereinbefore may be applied as asole therapy or may involve, in addition to the compound of theinvention, conventional surgery or radiotherapy or chemotherapy. Suchchemotherapy may include one or more of the following categories ofanti-tumour agents:—

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumourantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of 5α-reductase suchas finasteride;(iii) anti-invasion agents [for example c-Src kinase family inhibitorslike4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline(AZD0530; International Patent Application WO 01/94341),N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) andbosutinib (SKI-606), and metalloproteinase inhibitors like marimastat,inhibitors of urokinase plasminogen activator receptor function orantibodies to Heparanase];(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab[Erbitux, C₂₂₅] and any growth factor or growth factor receptorantibodies disclosed by Stern et al. (Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);inhibitors of the hepatocyte growth factor family; inhibitors of theinsulin growth factor family; inhibitors of the platelet-derived growthfactor family such as imatinib and/or nilotinib (AMN107); inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006),tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cellsignalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinaseinhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinaseinhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors;aurora kinase inhibitors (for example AZD1152, PH739358, VX-680,MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependentkinase inhibitors such as CDK2 and/or CDK4 inhibitors;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and forexample, a VEGF receptor tyrosine kinase inhibitor such as vandetanib(ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736),pazopanib (GW 786034) and4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(AZD2171; Example 240 within WO 00/47212), compounds such as thosedisclosed in International Patent Applications WO97/22596, WO 97/30035,WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms(for example linomide, inhibitors of integrin αvβ3 function andangiostatin)];(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) an endothelin receptor antagonist, for example zibotentan (ZD4054)or atrasentan;(viii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;(ix) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and(x) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

In a particular embodiment, the antiproliferative treatment definedhereinbefore may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

According to this aspect of the invention there is provided acombination for use in the treatment of a cancer (for example a cancerinvolving a solid tumour) comprising a compound of the invention asdefined hereinbefore, or a pharmaceutically acceptable salt, hydrate orsolvate thereof, and another anti-tumour agent.

According to this aspect of the invention there is provided acombination for use in the treatment of a proliferative condition, suchas cancer (for example a cancer involving a solid tumour), comprising acompound of the invention as defined hereinbefore, or a pharmaceuticallyacceptable salt, hydrate or solvate thereof, and any one of theanti-tumour agents listed herein above.

In a further aspect of the invention there is provided a compound of theinvention or a pharmaceutically acceptable salt, hydrate or solvatethereof, for use in the treatment of cancer in combination with anotheranti-tumour agent, optionally selected from one listed herein above.

Herein, where the term “combination” is used it is to be understood thatthis refers to simultaneous, separate or sequential administration. Inone aspect of the invention “combination” refers to simultaneousadministration. In another aspect of the invention “combination” refersto separate administration. In a further aspect of the invention“combination” refers to sequential administration. Where theadministration is sequential or separate, the delay in administering thesecond component should not be such as to lose the beneficial effect ofthe combination. In one embodiment, a combination refers to acombination product.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the invention,or a pharmaceutically acceptable salt, hydrate or solvate thereof, incombination with an anti-tumour agent (optionally selected from onelisted herein above), in association with a pharmaceutically acceptablediluent or carrier.

EXAMPLES Chemistry

The following examples are provided solely to illustrate the presentinvention and are not intended to limit the scope of the invention, asdescribed herein.

The compounds of the invention may be prepared using synthetictechniques that are known in the art (as illustrated by the examplesherein).

For convenience, the following common abbreviations are used herein:

-   Boc for tert-butyloxycarbonyl-   DAST for diethylaminosulfur trifluoride-   DBU for 1,8-diazabicyclo(5.4.0)undec-7-ene-   DCM for dichloromethane-   DEA for diethanolamine-   DIPEA for N,N-diisopropylethylamine, Hünig's base-   DMA for N,N-dimethylacetamide-   DMF for N,N-dimethylformamide-   DMSO for dimethylsulfoxide.-   h for hours-   HBTU for O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HPLC for High Pressure Liquid Chromatography.-   IPA for isopropyl alcohol-   LCMS for Liquid Chromatography-Mass Spectrometry.-   MI for Molecular Ion-   Min for minutes-   MW for microwave-   NBS for N-bromosuccinamide-   NCS for N-chlorosuccinamide-   NIS for N-iodosuccinamide-   NMM for N-methylmorpholine-   NMP for 1-methyl-2-pyrrolidinone-   NMR for Nuclear Magnetic Resonance.-   p-TSA for para-toluenesulfonic acid-   Pd(dppf)C₂ for    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Pd(dba)₂ for bis(dibenzylideneacetone)palladium-   RT for Retention Time.-   SCX-2 for a silica-based sorbent with a chemically bonded    propylsulfonic acid functional group-   SFC for supercritical fluid chromatography-   TBME for tert-butylmethyl ether-   TFA for trifluoroacetic acid-   THF for tetrahydrofuran-   THP for tetrahydropyran

General Methods: NMR

Proton NMR spectra were recorded using a Bruker AMX-300 NMR machine at300 MHz, a Bruker AMX-400 NMR machine at 400 MHz or a Bruker Avance 500machine at 500 MHz. Shifts were reported in ppm values relative to aninternal standard of tetramethylsilane (TMS) or residual protic solvent.The following abbreviations were used to describe the splittingpatterns: s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), dd (double-doublet), dt (double-triplet), br (broad).

General Methods: LCMS Methods Method: 1 LCMS1

Method 1LCMS1 employed Waters 515 pumps, a Waters 2525 mixer with valvesdirecting to the different columns and a Waters 2487 diode arraydetector. The detection was performed at 254 nm. The mass spectrometerwas a Waters micromass ZQ which detected masses between 100 and 700g/mol. The column used was a SunFire, 5 micron pore size, C18 column ofdimensions 50×4.60 mm. The injection volume was 10 μL at a maximumconcentration of 1 mg/mL. The flow rate was 1.5 mL/min and the mobilephases of water and methanol contained 0.1% formic acid. The elution wasstarted at 85% water:15% methanol ramping up to 15% water:85% methanolover 4.5 minutes, these conditions were held for 1 minute before theeluent level was returned to the starting conditions of 85% water:15%methanol over 6 seconds. These conditions were held for 1.4 minutes toallow equilibration of the column before the next sample was injected.The run lasted 7 minutes in total.

Method: 1 LCMS12

Method 1LCMS12 employed Waters 515 pumps, a Waters 2525 mixer withvalves directing to the different columns and a Waters 2998 diode arraydetector. The detection was performed between 210 nm and 400 nm. Themass spectrometer was a Waters micromass ZQ which detected massesbetween 100 and 700 g/mol. The column used was a SunFire, 5 micron poresize, C18 column of dimensions 50×4.60 mm. The injection volume was 10μL at a maximum concentration of 1 mg/mL. The flow rate was 1.5 mL/minand the mobile phases of water and acetonitrile contained 0.1% formicacid. The elution was started at 95% water:5% acetonitrile ramping up to5% water:95% acetonitrile over 5 minutes, these conditions were held for0.5 min before the eluent level was returned to the starting conditionsof 95% water:5% acetonitrile over 6 seconds. These conditions were heldfor 1.4 minutes to allow equilibration of the column before the nextsample was injected. The run lasted 7 minutes in total.

Method: 1 LCMS13

Method 1LCMS13 employed Waters 515 pumps, a Waters 2525 mixer withvalves directing to the different columns and a Waters 2998 diode arraydetector. The detection was performed between 210 nm and 400 nm. Themass spectrometer was a Waters micromass ZQ which detected massesbetween 100 and 700 g/mol. The column used was a SunFire, 5 micron poresize, C18 column of dimensions 50×4.60 mm. The injection volume was 10μL at a maximum concentration of 1 mg/mL. The flow rate was 1.5 mL/minand the mobile phases of water and acetonitrile contained 0.1% formicacid. The elution was started at 95% water:5% acetonitrile ramping up to5% water:95% acetonitrile over 2.5 minutes, these conditions were heldfor 3 min before the eluent level was returned to the startingconditions of 95% water:5% acetonitrile over 18 seconds. Theseconditions were held for 1.2 minutes to allow equilibration of thecolumn before the next sample was injected. The run lasted 7 minutes intotal.

Method: 2LCMS1

Method 2LCMS1 employed Waters 515 pumps, a Waters 2545 mixer with valvesdirecting to the different columns and a Waters 2996 diode arraydetector. The detection was performed between 210 nm and 650 nm. Themass spectrometer was a Waters 3100 which detected masses between 100and 700 g/mol. The column used was an XBridge, 5 micron pore size, C18,50×4.60 mm. The injection volume was 10 μL at a maximum concentration of1 mg/mL. The flow rate was 1.5 mL/min and the mobile phases of water pH10 (35% ammonia solution (aq) 0.3 mL/L) and methanol (35% ammoniasolution (aq) 0.3 mL/L). The elution was started at 85% water:15%methanol ramping up to 15% water:85% methanol over 4.5 minutes. Theseconditions were held for 1 minute before the eluent level was returnedto the starting conditions of 85% water:15% methanol over 6 seconds.These conditions were held for 1.4 minutes to allow equilibration of thecolumn before the next sample was injected. The run lasted 7 minutes intotal.

Method: 2LCMS5

Method 2LCMS5 employed Waters 515 pumps, a Waters 2545 mixer with valvesdirecting to the different columns and a Waters 2996 diode arraydetector. The detection was performed between 210 nm and 650 nm. Themass spectrometer was a Waters 3100 which detected masses between 100and 700 g/mol. The column used was an XBridge, 5 micron pore size, C18,50×4.60 mm. The injection volume was 10 μL at a maximum concentration of1 mg/mL. The flow rate was 1.5 mL/min and the mobile phases of water pH10 (35% ammonia solution (aq) 0.3 mL/L) and acetonitrile (35% ammoniasolution (aq) 0.3 mL/L). The elution was started at 95% water:5%acetonitrile ramping up to 5% water:95% acetonitrile over 5 minutes.These conditions were held for 0.5 minutes before the eluent level wasreturned to the starting conditions of 95% water:5% acetonitrile over 18seconds. These conditions were held for 1.2 minutes to allowequilibration of the column before the next sample was injected. The runlasted 7 minutes in total.

Method: 4LCMS1

Method 4LCMS1 employed an Alliance e2695 liquid handler and SFO with aWaters 2998 diode array detector. The detection was done at 254 nm andan array between 210-600 nm. The mass spectrometer used was an AcquitySQ which detected masses between 100 and 700 g/mol. The column used wasa SunFire, 5 micron pore size, C18 column of dimensions 50×4.60 mm. Theinjection volume was 10 μL at a maximum concentration of 1 mg/mL. Theflow rate was 1.5 mL/min and the mobile phases of water and acetonitrilecontained 0.1% formic acid. The elution was started at 95% water:5%acetonitrile ramping up to 5% water:95% acetonitrile over 5 minutes,these conditions were held for 0.5 min before the eluent level wasreturned to the starting conditions of 95% water:5% acetonitrile over 6seconds. These conditions were held for 1.4 minutes to allowequilibration of the column before the next sample was injected. The runlasted 7 minutes in total.

Method: 4LCMS3

Method 4LCMS3 employed an Alliance e2695 liquid handler and SFO with aWaters 2998 diode array detector. The detection was done at 254 nm andan array between 210-600 nm. The mass spectrometer used was an AcquitySQ which detected masses between 100 and 700 g/mol. The column used wasa SunFire, 5 micron pore size, C18 column of dimensions 50×4.60 mm. Theinjection volume was 10 μL at a maximum concentration of 1 mg/mL. Theflow rate was 1.5 mL/min and the mobile phases of water and acetonitrilecontained 0.1% formic acid. The elution was started at 95% water:5%acetonitrile ramping up to 5% water:95% acetonitrile over 2.25 minutes,these conditions were held for 2.8 min before the eluent level wasreturned to the starting conditions of 95% water:5% acetonitrile over 6seconds. These conditions were held for 0.8 minutes to allowequilibration of the column before the next sample was injected. The runlasted 3.7 minutes in total.

Method: 4LCMS6

Method 4LCMS6 employed an Alliance e2695 liquid handler and SFO with aWaters 2998 diode array detector. The detection was done at 254 nm andan array between 210-600 nm. The mass spectrometer used was an AcquitySQ which detected masses between 100 and 700 g/mol. The column used wasa Waters Cortecs, 2.7 micron pore size, C18 column of dimensions 50×4.60mm used at a temperature of 45° C. The injection volume was 10 μL at amaximum concentration of 1 mg/mL. The flow rate was 2.2 mL/min and themobile phases of water and acetonitrile contained 0.1% formic acid. Theelution was started at 95% water:5% acetonitrile ramping up to 5%water:95% acetonitrile over 2.2 minutes, these conditions were held for2.5 min before the eluent level was returned to the starting conditionsof 95% water:5% acetonitrile over 6 seconds. These conditions were heldfor 0.6 minutes to allow equilibration of the column before the nextsample was injected. The run lasted 3.2 minutes in total.

Method: 5LCMS1

Method 5LCMS1 employed Waters 515 pumps, a Waters 2525 mixer with valvesdirecting to the different columns and a Waters 2998 diode arraydetector. The detection was performed at 254 nm and an array between210-600 nm. The mass spectrometer used was a Waters 3100 which detectedmasses between 100 and 700 g/mol. The column used was a SunFire, 5micron pore size, C18 column of dimensions 50×4.60 mm. The injectionvolume was 10 μL at a maximum concentration of 1 mg/mL. The flow ratewas 1.5 mL/min and the mobile phases of water and acetonitrile contained0.1% formic acid. The elution was started at 95% water:5% acetonitrileramping up to 5% water:95% acetonitrile over 5 minutes, these conditionswere held for 0.5 min before the eluent level was returned to thestarting conditions of 95% water:5% acetonitrile over 6 seconds. Theseconditions were held for 1.4 minutes to allow equilibration of thecolumn before the next sample was injected. The run lasted 7 minutes intotal.

Synthesis

Several methods for the chemical synthesis of the present applicationare described herein. These and/or other well-known methods may bemodified and/or adapted in various ways in order to facilitate thesynthesis of additional compounds within the scope of the presentapplication and claims. Such alternative methods and modificationsshould be understood as being within the spirit and scope of thisapplication and claims. Accordingly, it should be understood that themethods set forth in the following descriptions, schemes and examplesare intended for illustrative purposes and are not to be construed aslimiting the scope of the disclosure.

In one approach (General Scheme 1), compounds of formula [F1-3] areprepared by the reaction of a 3-substituted β-ketopropyl ester compoundof formula [F1-1] in a condensation reaction utilising a suitablysubstituted heterocyclic carboximidamide derivative of general formula[F1-2] in a polar solvent such as methanol or THF in the presence of abase such as sodium methoxide or DBU. The reaction is suitably conductedat ambient temperature or at high temperature either by heatingthermally or using a microwave reactor. After reaction work up,typically by a liquid-liquid extraction, the reaction product was usedcrude in the next step or purified by flash column chromatography,reverse phase preparative HPLC or re-crystallisation. Derivatives ofgeneral formula [F1-5] are prepared by the reaction of compounds offormula [F1-3] with a halogenating agent such as NCS or NBS in a polarsolvent such as DMF or THF and a base such as Et₃N or DIPEA at ambienttemperature. After reaction work up, typically by a liquid-liquidextraction, the reaction product was used crude in the next step orpurified by flash column chromatography, reverse phase preparative HPLCor re-crystallisation.

Alternatively, compounds of formula [F1-5] are prepared by the reactionof a 2,3-disubstituted β-ketopropyl ester compound of formula [F1-4] ina condensation reaction utilising a suitably substituted heterocycliccarboximidamide derivative of general formula [F1-2] in a polar solventsuch as methanol or THF in the presence of a base such as sodiummethoxide or DBU. The reaction is suitably conducted at ambienttemperature or at high temperature either by heating thermally or usinga microwave reactor. After reaction work up, typically by aliquid-liquid extraction, the reaction product was used crude in thenext step or purified by flash column chromatography, reverse phasepreparative HPLC or re-crystallisation.

In cases where the substituent R² contained an amine protected by astandard amine protecting group such as tert-butyloxycarbonyl (Boc),compounds of formula [F1-5] can be deprotected by a suitabledeprotection reaction, for example reaction with an acid such as TFA ina suitable solvent such as DCM at ambient temperature. After reactionwork up, typically by a liquid-liquid extraction or purification byacidic ion exchange catch-release the crude product can be purified byflash column chromatography, reverse phase preparative HPLC orre-crystallisation.

Synthesis of 4-methylthiazole-5-carboxamidine hydrochloride (1-001)

Ammonium chloride (7.81 g, 146 mmol) was suspended in toluene (50 mL)under nitrogen and cooled to 0° C. Trimethylaluminium solution (2.0 M intoluene, 62.5 mL, 125 mmol) was added dropwise to the reaction mixturekeeping the temperature below 10° C. Once the addition was completed,the reaction mixture was allowed to warm to room temperature and stirredfor 1 hour. The reaction was then heated to reflux for 18 h beforecooling to room temperature. Ethyl 4-methyl-1,3-thiazole-5-carboxylate(2.50 g, 14.6 mmol) was added and the reaction heated to reflux for 7hours. The reaction mixture was cooled to room temperature and anotherbatch of ethyl 4-methyl-1,3-thiazole-5-carboxylate (2.50 g, 14.6 mmol)was added. The reaction mixture was heated to reflux for 18 h thencooled to room temperature and another batch of ethyl4-methyl-1,3-thiazole-5-carboxylate (2.50 g, 14.6 mmol) was added. Thereaction was heated to reflux for a further 24 h then cooled to roomtemperature. The reaction mixture was added slowly to MeOH (100 mL)under vigorous stirring (exotherm observed). The obtained thickprecipitate was filtered onto a glass fibre filtration sheet under anitrogen flow. The pad was washed with MeOH and the combined filtratewas concentrated under vacuum. The residue was sonicated for 15 min inDCM (50 mL), then stirred vigorously to break up the crystals. Thesuspension was filtered through a sintered funnel to give an off-whitesolid. The collected solid was dried in a vacuum oven at 50° C. for 1 hto afford the title compound (4.0 g, 51%). LCMS: MI 143, Method(1LCMS1); ¹H NMR (500 MHz, DMSO-d₆) δ 9.51 (br s, 3H), 9.30 (s, 1H),7.70 (br s, 3H), 2.54 (s, 3H).

Synthesis of tert-butyl4-[5-chloro-2-(4-methylthiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]piperidine-1-carboxylate(1-002)

4-Methylthiazole-5-carboxamidine hydrochloride (1-001) (2.00 g, 14.2mmol) was dissolved in MeOH (50 mL) andtert-butyl-4-(3-ethoxy-3-oxopropanoyl)tetrahydro-1(2H)-pyridinecarboxylate(4.24 g, 14.2 mmol) was added, followed by DBU (8.47 mL, 56.7 mmol). Thereaction mixture was heated to reflux for 24 h. The reaction mixture wasthen concentrated under vacuum and the residue suspended in EtOAc (20mL) then sonicated. The precipitate obtained was collected by vacuumfiltration. The solid collected was partitioned between DCM and 1 N HClsolution (aq). The organic phase was separated, dried (MgSO₄), filteredand concentrated under vacuum to give the title compound (2.59 g, 49%).¹H NMR (300 MHz, CDCl₃) δ 11.93 (br s, 1H), 8.83 (s, 1H), 6.21 (s, 1H),4.23 (br s, 2H), 2.89-2.72 (m, 5H), 2.68-2.55 (m, 1H), 1.90 (d, J=12.9Hz, 2H), 1.65 (qd, J=12.4, 4.3 Hz, 2H), 1.47 (s, 9H).

Synthesis of tert-butyl4-[5-chloro-2-(4-methylthiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]piperidine-1-carboxylate(1)

tert-Butyl4-[5-chloro-2-(4-methylthiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]piperidine-1-carboxylate(1-002) (2.00 g, 5.31 mmol) in glacial acetic acid (50 mL) was treatedwith NCS (0.850 g, 6.37 mmol) and heated to reflux for 5 h. The reactionmixture was allowed to cool to room temperature then added to ice (50mL). The resulting mixture was extracted with DCM. The aqueous phase wasfurther extracted with DCM. The combined organic phases were dried(MgSO₄), filtered and concentrated under vacuum. The residue wasdissolved in a minimum volume of DCM and was purified by columnchromatography on silica gel, eluting with MeOH in DCM (0 to 5%).Fractions of interest were combined and concentrated under vacuum togive the title compound (0.194 g, 9%). LCMS: RT 3.58 min, MI 411, Method(1LCMS1); ¹H NMR (300 MHz, CDCl₃) δ 12.11 (s, 1H), 8.86 (s, 1H), 4.25(s, 2H), 3.38-3.15 (m, 1H), 3.00-2.58 (m, 5H), 1.98-1.61 (m, 4H), 1.48(s, 9H).

Synthesis of5-chloro-2-(4-methylthiazol-5-yl)-4-(4-piperidyl)-1H-pyrimidin-6-one (2)

tert-Butyl4-[5-chloro-2-(4-methylthiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]piperidine-1-carboxylate(1) (0.634 g, 1.544 mmol) was taken into DCM (20 mL) and HCl in dioxane(4 M, 0.385 mL) was added. The reaction mixture was stirred at roomtemperature for 18 h, followed by 45° C. for 18 h. The reaction mixturewas allowed to cool to room temperature then concentrated under a flowof nitrogen. The residue was partitioned between DCM and saturatedaqueous NaHCO₃ solution. The DCM phase was washed with brine, dried(MgSO₄), filtered and concentrated under vacuum to give the titlecompound (0.437 g, 91%). LCMS: RT 2.16 min, MI 311, Method (1LCMS1); ¹HNMR (300 MHz, DMSO-d₆) δ 9.13 (s, 1H), 3.36 (d, J=11.6 Hz, 3H), 3.05 (s,2H), 2.72 (s, 3H), 1.94 (d, J=26.0 Hz, 4H).

Synthesis of2-(4-methylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(1-003)

In a 50 mL round bottom flask equipped with a condenser, under nitrogen,was added 4-methylthiazole-5-carboxamidine; hydrochloride (1-001) (0.502g, 2.82 mmol) in MeOH (10 mL). This was treated with3-oxo-3-tetrahydropyran-4-yl propionic acid ethyl ester (0.568 g, 2.82mmol) followed by DBU (1.69 mL, 11.3 mmol) and the reaction mixturestirred at 65° C. for 18 h. The reaction mixture was then concentratedunder vacuum. The residue was dissolved in a minimum volume of DCM andpurified by flash column chromatography on silica gel, eluting with MeOHin DCM (0 to 5%). The appropriate fractions were concentrated undervacuum and the residue was suspended in EtOAc and then sonicated for 5min. The suspension was collected by vacuum filtration onto a sinteredfunnel to give the title compound (0.486 g, 62%). LCMS: RT 3.52 min, MI278, Method (1LCMS1). ¹H NMR (300 MHz, DMSO-d₆) δ 12.11 (br s, 1H), 9.04(s, 1H), 6.37 (s, 1H), 3.93 (d, J=10.7 Hz, 2H), 3.49-3.34 (m, 2H),2.87-2.70 (m, 4H), 1.83-1.62 (m, 4H).

Synthesis of5-bromo-2-(4-methylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(3)

2-(4-Methylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(1-003) (27.7 mg, 0.100 mmol) was suspended in DCM (1 mL). NBS (200 mg,0.110 mmol) was added, followed by Et₃N (0.100 mL, 0.719 mmol) and thereaction allowed to stir overnight at room temperature. The mixture wasconcentrated under reduced pressure and the residue purified bypreparative HPLC to give the title compound (23 mg, 65%). LCMS: RT 3.11min, MI 357, Method (1LCMS1); ¹H NMR (300 MHz, CDCl₃) δ 8.88 (S, 1H),4.10 (dd, J=11.4, 3.8 Hz, 2H), 3.57 (t, J=11.5 Hz, 2H), 3.37 (td, J=9.8,8.0, 6.0 Hz, 1H), 2.87 (s, 3H), 2.03 (qd, J=12.5, 4.3 Hz, 2H), 1.71 (d,J=12.6 Hz, 2H).

Synthesis of 2-fluoro-3-oxo-3-(tetrahydro-pyran-4-yl)-propionic acidethyl ester (1-004)

3-Oxo-3-tetrahydropyran-4-yl propionic acid ethyl ester (1.00 g, 5.00mmol) and Selectfluor (1.95 g, 5.00 mmol) were combined in acetonitrile(10 mL). The reaction was allowed to stir at room temperature for 2days. The solvent was evaporated under reduced pressure and DCM (20 mL)was added to the residue. A solid precipitated out which was removed byfiltration. The filtrate was concentrated under reduced pressure and theresultant oil was purified by column chromatography (eluting with 0% DCMto 20% MeOH in DCM) to give the title compound (0.85 g, 78%). ¹H NMR(300 MHz, CDCl₃) δ 5.29 (d, J=49.3 Hz, 1H), 4.43-4.24 (m, 2H), 4.08-3.90(m, 2H), 3.56-3.33 (m, 2H), 3.21-3.01 (m, 1H), 1.90-1.55 (m, 4H),1.39-1.16 (m, 3H).

Synthesis of thiazole-5-carboxamidine (1-005)

Thiazole-5-carbonitrile (0.69 g, 6.30 mmol) was dissolved in methanol(15 mL) and treated with sodium methoxide (0.033 g, 0.63 mmol) and thentreated with ammonium chloride (0.33 g, 6.30 mmol). The reaction mixturewas allowed to stir at room temperature for 3 days and then the solventwas evaporated under reduced pressure to a pale yellow solid. Methanol(2 mL) was added followed by diethyl ether (20 mL). The resulting whiteprecipitate was filtered off and washed with diethyl ether (5 mL). Thesolid was dried under reduced pressure to yield the title compound (0.38g, 47%) as a white solid. LCMS: RT 0.53 min, MI 128, Method (4LCMS1).

Synthesis of 2-methyl-2H-pyrazole-3-carboxamidine (1-006)

Ammonium chloride (1.87 g, 35.0 mmol) was suspended in dry toluene (50mL) and azeotroped to dryness. The residue was placed under nitrogen anddissolved in toluene (30 mL). The suspension was cooled to 0° C. Thereaction mixture was treated dropwise with trimethylaluminium (2 M intoluene, 17.5 mL, 35.0 mmol), keeping the temperature below 10° C. Thereaction mixture was left to warm to room temperature and allowed tostir for three hours. 2-Methyl-2H-pyrazole-3-carboxylic acid ethyl ester(1.07 g, 7.00 mmol) was added to the reaction mixture and then heated at80° C. for 15 hours. The reaction mixture was quenched by the carefuladdition of methanol (40 mL) at 0° C. The reaction mixture was left tostir at room temperature for 30 min and the thick white cloudysuspension was filtered through celite to remove the excess aluminiumresidues. The filtrates were evaporated under reduced pressure to give awhite solid which was taken up in a minimum amount of methanol (10 mL).Diethyl ether was added (50 mL) to precipitate the excess aluminiumresidues which were then filtered off. The filtrates were concentratedunder reduced pressure to provide the title compound (0.58 g, 67%) as ayellow solid. LCMS: RT 0.56 min, MI 125, Method (5LCMS1); ¹H NMR (400MHz, DMSO-d₆) δ 9.41 (d, 3H), 7.65 (d, 1H), 6.86 (d, 1H), 3.99 (s, 3H).

Synthesis of 4-methyl-oxazole-5-carboxamidine (1-007)

Ammonium chloride was suspended in toluene and azeotroped on a rotaryevaporator. The ammonium chloride (1.59 g, 30.0 mmol) was weighed into a3-neck round bottom flask under a nitrogen atmosphere. Toluene (15 mL)was added and the suspension was cooled to 0° C. The reaction mixturewas treated dropwise with trimethylaluminium 2 M in toluene (15 mL, 30.0mmol). The reaction mixture was left to warm to room temperature andstirred for 3 hours. 4-Methyl-oxazole-5-carboxylic acid ethyl ester(0.465 g, 3.00 mmol) was added and the reaction mixture was heated at80° C. overnight. The reaction was cooled and quenched by slow additionof methanol (30 mL). A white solid precipitated which was then filteredoff through celite, washing with more methanol. The methanol was thenevaporated until approximately 5 mL was left. This was then treated withdiethyl ether (20 mL) and filtered again. The filtrate was thenevaporated to yield the title compound (0.34 g, 89%). ¹H NMR (400 MHz,DMSO-d₆) δ 9.52 (s, 2H), 9.35 (s, 2H), 8.78 (s, 1H), 2.41 (s, 3H).

Synthesis of 4-ethyl-thiazole-5-carboxamidine (1-008)

Ammonium chloride was suspended in toluene and azeotroped on a rotaryevaporator. The ammonium chloride (0.53 g, 10.0 mmol) was weighed into a3-neck round bottom flask under a nitrogen atmosphere. Toluene (5 mL)was added and the suspension was cooled to 0° C. The reaction mixturewas treated dropwise with trimethylaluminium 2 M in hexane (5 mL, 10.0mmol). The reaction mixture was left to warm to room temperature andstirred for 3 hours. Then 4-ethyl-thiazole-5-carboxylic acid ethyl ester(0.185 g, 1.00 mmol) was added and the reaction mixture was heated at80° C. overnight. The reaction was cooled and quenched by slow additionof methanol (30 mL). A white solid precipitated which was then filteredoff through celite, washing with more methanol. The methanol was thenevaporated until approximately 1 mL was left. This was then treated withdiethyl ether (5 mL) and filtered again. The residual solvent was thenevaporated to give the title compound (0.13 g, 81%) LCMS: RT solventfront, Method (4LCMS1).

Synthesis of 4-trifluoromethyl-thiazole-5-carboxamidine (1-009)

Ammonium chloride was suspended in toluene and azeotroped on a rotaryevaporator. The ammonium chloride (6.42 g, 120.0 mmol) was weighed intoa 3-neck round bottom flask under a nitrogen atmosphere. Toluene (60 mL)was added and the suspension was cooled to 0° C. The reaction mixturewas treated dropwise with trimethylaluminium 2 M in toluene (60 mL,120.0 mmol). The reaction mixture was left to warm to room temperatureand stirred for 3 hours. Then 4-trifluoromethyl-thiazole-5-carboxylicacid ethyl ester (2.70 g, 12.0 mmol) was added and the reaction mixturewas heated at 80° C. overnight. The reaction was cooled and quenched byslow addition of methanol (30 mL). A white solid precipitated which wasthen filtered off through celite, washing with more methanol. Themethanol was then evaporated until approximately 10 mL was left. Thiswas then treated with diethyl ether (50 mL) and filtered again. Theresidual solvent was evaporated to give the title compound (2.0 g, 85%).LCMS: RT solvent front, Method (4LCMS1).

Synthesis of 4-chloro-thiazole-5-carboxylic acid methyl ester (1-010)

A solution of methyl 2,4-dichlorothiazole-5-carboxylate (1.06 g, 5.00mmol) in AcOH (15 mL) was heated to reflux and zinc dust (1.00 g, 15.0mmol) was added. The mixture was stirred at reflux for 2 h. The mixturewas allowed to cool to room temperature before the addition of 2 Maqueous NaOH solution (90 mL), water (50 mL) and a saturated aqueoussolution of NaHCO₃ (60 mL) (a pH of approximately 7 was achieved). Themixture was extracted with DCM (2×200 mL) and the combined organicsdried and concentrated under reduced pressure. The residue was purifiedby flash chromatography on silica gel (eluting with 0-10% EtOAc incyclohexane) to afford the title compound (0.507 mg. 57%) as a whitesolid. LCMS: RT 3.40 min, MI 178, Method (4LCMS1).

Synthesis of 4-chloro-thiazole-5-carboxamidine (1-011)

Ammonium chloride was suspended in toluene and azeotroped. Ammoniumchloride (1.65 g, 30.9 mmol) was placed under nitrogen and dissolved intoluene (15 mL). The suspension was cooled to 0° C. The reaction mixturewas treated dropwise with trimethylaluminium 2 M in toluene (16 mL, 30.9mmol), carefully monitoring the temperature to −5 to 0° C. The reactionmixture was left to warm to room temperature and allowed to stir for 2.5hours. 4-Chloro-thiazole-5-carboxylic acid methyl ester (1-010) (0.549g, 3.09 mmol) in toluene (10 mL) was added and the mixture heated to 80°C. overnight under nitrogen. The mixture was cooled to 0° C. andquenched with the slow addition of MeOH (30 mL). The resultant whiteprecipitate was filtered through celite and washed with MeOH (70 mL).The filtrate was evaporated under reduced pressure. The residue wastriturated in methanol (10 mL) and the supernatant liquid collected bypipette. This was repeated 3 times. The combined supernatant liquidswere concentrated under reduced pressure. A mixture of MeOH:Et₂O (1:2ratio, 50 mL) was then added, the mixture filtered and the filtrateconcentrated under reduced pressure to give the title compound (0.386 g,77%) as a yellow solid. LCMS: RT 0.6 min, MI 162, Method (4LCMS1).

Synthesis of2-(4-chlorothiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(1-012)

4-Chloro-thiazole-5-carboxamidine (1-011) (0.385 g, 2.380 mmol) wasdissolved in MeOH (25 mL) and 3-oxo-3-(tetrahydro-pyran-4-yl)-propionicacid ethyl ester (0.524 g, 2.620 mmol) then DBU (0.71 mL, 4.760 mmol)added. The mixture was heated to reflux for 2 h. The reaction wasconcentrated under reduced pressure and the residue purified by flashchromatography on silica gel (eluting with 30% EtOAc/cyclohexane, then10% MeOH/DCM) to give the title compound (0.177 g, 25%) as an orangesolid. LCMS: RT 2.88 min, MI 298, Method (4LCMS1).

Synthesis of5-chloro-2-(4-chlorothiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(4)

To a solution of2-(4-chlorothiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(1-012) (0.176 g, 0.590 mmol) in MeCN (6 mL) was addedN-chlorosuccinamide (0.083 g, 0.620 mmol) and triethylamine (0.164 mL,1.180 mmol) and the mixture allowed to stir at room temperature undernitrogen for 4 h. Further NCS (30 mg) was added and the mixture allowedto stir at room temperature overnight. The reaction was concentratedunder reduced pressure, the residue dissolved in DCM (50 mL) and washedwith a saturated solution of disodium citrate (50 mL). The aqueous layerwas extracted with further DCM (50 mL). The combined organics were driedand concentrated under reduced pressure to afford an orange solid. Thiswas purified by preparative HPLC to give the title compound (0.120 g,60%). LCMS: RT 3.52 min, MI 332, Method (4LCMS1); ¹H NMR (400 MHz,DMSO-d₆) δ 9.25 (s, 1H), 3.96 (ddd, J=11.4, 4.5, 1.7 Hz, 2H), 3.46 (td,J=11.9, 2.0 Hz, 2H), 1.86 (ddt, J=16.7, 12.0, 6.0 Hz, 2H), 1.76-1.47 (m,3H).

Synthesis of 2-chloro-4-methyl-thiazole-5-carboxamidine (1-013)

Ammonium chloride was suspended in toluene and azeotroped on a rotaryevaporator. The ammonium chloride (4.81 g, 90.0 mmol) was weighed into a3-neck round bottom flask under a nitrogen atmosphere. Toluene (45 mL)was added and the suspension was cooled to 0° C. The reaction mixturewas treated dropwise with trimethylaluminium 2 M in hexane (45 mL, 90.0mmol). The reaction mixture was left to warm to room temperature andstirred for 3 hours. Then 2-chloro-4-methyl-thiazole-5-carboxylic acidmethyl ester (1.85 g, 9.00 mmol) was added and the reaction mixture washeated at 80° C. overnight. The reaction was cooled and quenched by slowaddition of methanol (30 mL). A white solid precipitated which was thenfiltered off through celite, washing with more methanol. The methanolwas then evaporated until approximately 1 mL was left. This was thentreated with diethyl ether (5 mL) and filtered again. The solvent wasthen evaporated to give the title compound (1.4 g, 89%). LCMS: MI 176,Method (4LCMS1).

Synthesis of2-(2-chloro-4-methyl-thiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(1-014)

2-Chloro-4-methyl-thiazole-5-carboxamidine (1-013) (0.79 g, 4.50 mmol)was dissolved in IPA (50 mL) and treated with3-oxo-3-(tetrahydro-pyran-4-yl)-propionic acid ethyl ester (0.837 g,4.50 mmol) and DBU (1.77 mL, 13.5 mmol), this was stirred at roomtemperature under nitrogen overnight. The reaction mixture was thenevaporated and the resulting oil re-dissolved in DCM and washed withsaturated sodium citrate to yield the title compound (1.05 g, 75%) as anorange solid. LCMS: RT 3.74 min, MI 312, Method (4LCMS1).

Synthesis of5-chloro-2-(2-chloro-4-methyl-thiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(1-015)

2-(2-chloro-4-methyl-thiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(1-014) (0.624 g, 2.00 mmol) was dissolved in DCM (10 mL) and treatedwith NCS (0.60 g, 4.50 mmol) followed by triethylamine (0.60 mL, 4.50mmol) and left to stir for 30 minutes. The reaction mixture was thenwashed with saturated sodium citrate and then evaporated. This was thenpurified by flash chromatography on silica gel (eluting with 0-100%ethyl acetate in hexane), and then fractions containing the product wereevaporated to give the title compound (0.60 g, 87%). LCMS: RT 4.29 min,MI 346, Method (4LCMS1).

Synthesis of5-chloro-2-(2-hydroxy-4-methyl-thiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(5)

5-chloro-2-(2-chloro-4-methyl-thiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(1-015) (0.172 g, 0.500 mmol) was dissolved in THF (5 mL) and treatedwith aqueous sodium hydroxide (5 mL) and heated in the microwave to 100°C. for 1 hour. This was then acidified to pH 5 and extracted with DCM.The product remained in the aqueous layer which was then evaporatedunder reduced pressure and the residue re-dissolved in DMSO thenfiltered. This was then purified by preparative HPLC. The fractionscontaining the product were then combined and evaporated to give thetitle compound (0.03 g, 19%) LCMS: RT 3.08 min, MI 328, Method (4LCMS1);¹H NMR (400 MHz, DMSO-d₆) δ 12.88 (s, 1H), 11.70 (s, 1H), 3.97 (dd,J=11.3, 3.4 Hz, 2H), 3.47 (t, J=11.0 Hz, 2H), 3.35 (s, 3H), 3.30 (dt,J=7.9, 3.8 Hz, 1H), 1.81 (qd, J=12.7, 12.2, 4.4 Hz, 2H), 1.64 (d, J=11.2Hz, 2H).

The following compounds were synthesised according to the generalsynthesis shown in scheme [1]:

General formula of Starting No Material Product [F1-5] Characterisation6 F1-1

RT 4.42 min, MI 312/314, Method (1LCMS1); ¹H NMR (300 MHz, DMSO-d₆) δ13.17 (br s, 1H), 9.11 (s, 1H), 3.99-3.89 (m, 2H), 3.45 (td, J = 11.9,2.1 Hz, 2H), 3.39-3.25 (m, 1H), 2.73 (s, 3H), 1.82 (qd, J = 12.4, 4.4Hz, 2H), 1.69- 1.57 (m, 2H). 7 F1-1

RT 3.27 min, MI 404, Method (1LCMS1); ¹H NMR (300 MHz, CDCl₃) δ 8.87 (s,1H), 4.10 (dd, J = 11.2, 4.0 Hz, 2H), 3.57 (t, J = 11.2 Hz, 2H),3.50-3.34 (m, 1H), 2.86 (s, 3H), 2.04 (qd, J = 12.7, 4.8 Hz, 2H), 1.70(d, J = 13.2 Hz, 2H). 8 F1-4

RT 2.97 min, MI 296, Method (1LCMS1); ¹H NMR (300 MHz, CDCl₃) δ 8.87 (s,1H), 4.20- 3.95 (m, 2H), 3.57 (t, J = 11.9 Hz, 2H), 3.38- 3.12 (m, 1H),2.84 (s, 3H), 2.17-1.90 (m, 2H), 1.67 (d, J = 13.6 Hz, 2H). 9 F1-1

RT 3.14 min, MI 297/299, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ13.57 (s, 1H), 9.32 (s, 1H), 8.81 (s, 1H), 3.96 (d, J = 8.3 Hz, 2H),3.46 (t, J = 11.0 Hz, 2H), 3.30-3.22 (m, 1H), 1.83 (d, J = 8.5 Hz, 2H),1.60 (d, J = 11.5 Hz, 2H). 10 F1-1

RT 3.09 min, MI 294/296, Method (5LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ13.21(br s, 1H), 7.57 (d, 1H), 7.19 (d, 1H), 4.20 (s, 3H), 4.04-3.90 (m,2H), 3.47 (td, 2H), 3.32-3.26 (m, 1H, partially obscured by water),1.97- 1.77 (m, 2H), 1.72-1.58 (m, 2H). 11 F1-1

RT 3.69 min, MI 313, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 13.67(s, 1H), 3.98 (ddd, J = 11.4, 4.5, 1.7 Hz, 2H), 3.49 (td, J = 11.9, 2.1Hz, 2H), 3.44-3.36 (m, 1H), 3.01 (s, 3H), 1.94-1.75 (m, 2H), 1.69 (ddd,J = 12.7, 4.0, 1.9 Hz, 2H). 12 F1-1

RT 3.04 min, MI 296, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 13.30(s, 1H), 8.59 (s, 1H), 3.96 (dd, J = 11.5, 4.1 Hz, 2H), 3.51-3.42 (m,2H), 3.33-3.25 (m, 1H), 2.55 (s, 3H), 1.84 (qd, J = 12.5, 4.5 Hz, 2H),1.64 (d, J = 11.5 Hz, 2H). 13 F1-1

RT 3.44 min, MI 326, Method (4LCMS1); ¹H NMR (400 MHz, CDCl₃) δ 8.88 (s,1H), 4.11 (dd, J = 11.2, 3.6 Hz, 2H), 3.58 (td, J = 12.3, 1.9 Hz, 2H),3.41 (tt, J = 11.7, 3.7 Hz, 1H), 3.23 (q, J = 7.5 Hz, 2H), 2.04 (qd, J =12.4, 4.4 Hz, 2H), 1.76-1.64 (m, 2H), 1.40 (t, J = 7.5 Hz, 3H). 14 F1-1

RT 3.81 min, MI 365, Method (4LCMS1). ¹H NMR (400 MHz, DMSO-d₆) δ 13.67(s, 1H), 9.35 (s, 1H), 3.94 (dd, J = 11.3, 3.4 Hz, 2H), 3.45 (td, J =12.2, 1.7 Hz, 2H), 3.41-3.26 (m, 1H), 1.81 (qd, J = 12.6, 4.4 Hz, 2H),1.66- 1.51 (m, 2H).

Synthesis of 5-ethyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-4-carboxylicacid methyl ester (1-016)

5-Ethyl-1H-pyrazole-4-carbonitrile (0.150 g, 1.00 mmol) was weighed intoa round bottom flask and dissolved in THF (5 mL). To the solution wasadded 3,4-dihydro-2H-pyran (0.120 g, 1.50 mmol), molecular sieves andp-toluenesulfonic acid monohydrate (90.02 g, 0.100 mmol). The reactionmixture was heated at reflux for 1 hour and then cooled to roomtemperature. The solvent was removed under reduced pressure and DCM (20mL) was added and water (20 mL). The organics were collected, dried withMgSO₄, filtered and evaporated to yield the title compound (90.21 g,87%) as a white solid. LCMS: RT 4.13 min, MI 239, Method (4LCMS1); ¹HNMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 5.36-5.19 (m, 1H), 4.08 (d, J=10.4Hz, 1H), 3.81 (s, 3H), 3.76-3.60 (m, 1H), 2.90 (q, J=7.5 Hz, 2H),2.15-1.95 (m, 3H), 1.85-1.45 (m, 3H), 1.25 (t, 3H).

Synthesis of5-ethyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-4-carboxamidine (1-017)

Ammonium chloride (0.48 g, 9.00 mmol) was suspended in toluene andazeotroped on a rotary evaporator and then transferred into a 3 neckround bottom flask and placed under a nitrogen atmosphere. Toluene (5mL) was added and the suspension was cooled to 0° C. The reactionmixture was treated dropwise with trimethylaluminium 2 M in toluene (4.5mL, 9.00 mmol). The reaction mixture was left to warm to roomtemperature and stirred for 3 hours. Then5-ethyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-4-carboxylic acid methylester (1-016) (0.21 g, 0.90 mmol) was added in toluene (2 mL) and thereaction mixture was heated at 80° C. for 15 hours. The reaction mixturewas cooled to 0° C. and treated cautiously with methanol (5 mL). Thereaction mixture was left to stir for 30 minutes and then filteredthrough celite washing with methanol. The filtrates were evaporatedunder reduced pressure to yield a white solid. This was taken up in theminimum amount of methanol and treated with diethyl ether (10 mL) toprecipitate a white solid which was filtered off and discarded. Theprocess was repeated again on the filtrates and evaporation underreduced pressure yielded the title compound (0.11 g, 55%) as a paleyellow gum. LCMS: RT 1.60 min, MI 223, Method (4LCMS1).

Synthesis of2-(5-ethyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(1-018)

5-Ethyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazole-4-carboxamidine (1-017)(0.11 g, 0.50 mmol) was dissolved in methanol (5 mL) and treated with3-oxo-3-(tetrahydro-pyran-4-yl)-propionic acid ethyl ester (0.069 g,0.50 mmol) and DBU (0.15 mL, 1.00 mmol). The reaction mixture was heatedat reflux for 4 hours and then allowed to cool to room temperature andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (eluting with 95:5 DCM:MeOH) to yield the titlecompound (0.14 g, 77%) as a white solid. LCMS: RT 3.38 min, MI 359/360,Method (4LCMS1).

Synthesis of5-chloro-2-(5-ethyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(1-019)

2-(5-ethyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(1-018) (0.14 g, 0.40 mmol) was dissolved in dichloromethane (2 mL) andtriethylamine (0.14 mL, 1.00 mmol) and treated with N-chlorosuccinamide(0.13 g, 1.00 mmol). The reaction mixture was allowed to stir at roomtemperature for 15 hours. Saturated aqueous NH₄Cl solution was added (10mL) and the organics were separated. The organics were dried with MgSO₄,filtered and evaporated to yield an orange solid. This was purified byflash column chromatography (eluting with DCM then 95:5 DCM:MeOH) togive the title compound (0.15 g, 93%) as a pale yellow solid. LCMS: RT4.02 min, MI 393/395, Method (4LCMS1).

Synthesis of5-chloro-2-(5-ethyl-1H-pyrazol-4-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(15)

5-chloro-2-(5-ethyl-1-tetrahydropyran-2-yl-pyrazol-4-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(1-019) (0.15 g, 0.40 mmol) was suspended in methanol (15 mL) andtreated with p-TSA (0.010 g, 0.004 mmol). The reaction mixture wasallowed to stir at room temperature for 2 days. Further methanol (10 mL)was added to dissolve the solid and further p-TSA (5 mg, 0.002 mmol)added. The resultant solution was left to stir for 3 days at roomtemperature. The solvent was removed under reduced pressure and theresidue was dissolved in DCM (20 mL) and washed with aqueous NH₄Clsolution (20 mL). The organics were passed through a phase separationcartridge and evaporated under reduced pressure. The residue waspurified by mass directed LCMS. The fractions were evaporated to yieldthe title compound (0.016 g, 13%) as an off white solid. LCMS: RT 3.11min, MI 309/311, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 12.77 (s,1H), 8.36 (s, 1H), 3.95 (dd, J=11.2, 3.7 Hz, 2H), 3.55-3.39 (m, 2H),3.29 (dd, J=25.7, 14.0 Hz, 1H), 3.03 (q, J=7.4 Hz, 2H), 1.84 (dt,J=12.3, 8.3 Hz, 2H), 1.61 (d, J=10.9 Hz, 2H), 1.22 (t, J=7.5 Hz, 3H).

The following compounds were synthesised using a similar procedure tothat of compound (15) above, using an appropriately substitutedTHP-protected pyrazole:

No Product [F1-5] Characterisation 16

RT 2.92 min, MI 295 Method (4LCMS1) 17

RT 3.48 min, MI 348, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 14.07(s, 1H), 13.11 (s, 1H), 8.70 (s, 1H), 4.03-3.81 (m, 2H), 3.49-3.38 (m,2H), 3.26 (ddt, J = 11.6, 7.3, 3.6 Hz, 1H), 1.86 (qd, J = 12.6, 4.4 Hz,2H), 1.59-1.46 (m, 2H).

Synthesis of2-(4-methylthiazol-5-yl)-6-oxo-4-tetrahydropyran-4-yl-1H-pyrimidine-5-carbonitrile(18)

5-Iodo-2-(4-methylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one(7) (0.081 g, 0.200 mmol), Zn(CN)₂ (0.047 g, 0.400 mmol),Pd(PPh₃)₄(0.070 g, 0.060 mmol) and CuI (0.020 g, 0.100 mmol) werecombined in dry DMF (1 mL). The mixture was flushed with nitrogen,sealed and heated in the microwave for 30 min at 130° C. The suspensionwas diluted with MeOH and the resulting suspension was filtered throughcelite. The filtrate was concentrated under vacuum. The residue waspurified by reverse phase mass directed HPLC to give the title compound(2 mg, 3%). LCMS: RT 4.50 min, MI 303, Method (1LCMS1).

Synthesis of5-chloro-4-[1-(2,2-difluorocyclopropanecarbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one(19)

To a solution of 2,2-difluorocyclopropanecarboxylic acid (13.4 mg, 0.110mmol) in dry DMF (1 mL) was added DIPEA (87 μL, 0.250 mmol) followed byHBTU (57 mg, 0.150 mmol). The reaction mixture was placed undernitrogen, sealed then shaken for 15 minutes. A suspension of5-chloro-2-(4-methylthiazol-5-yl)-4-(4-piperidyl)-1H-pyrimidin-6-one (2)(35 mg, 0.100 mmol) in DMF (1 mL) and DIPEA (87 μL, 0.250 mmol) wasadded to the reaction mixture and the mixture was shaken for 1 h. Afterthis time, the mixture was purified by preparative HPLC to afford thetitle compound. LCMS: RT 4.47 min, MI 415.1/417.1, Method (1LCMS1); ¹HNMR (500 MHz, DMSO-d₆) δ 13.17 (s, 1H), 9.09 (s, 1H), 4.47 (d, J=13.1Hz, 1H), 4.25-4.08 (m, 1H), 3.47-3.09 (m, 3H), 2.87-2.74 (m, 1H),2.73-2.64 (m, 3H), 2.00-1.45 (m, 6H).

The following compounds were synthesised using a similar procedure tothat of compound (19) above:

No Product Characterisation 20

RT 4.12 min, MI 436, Method (1LCMS1); ¹H NMR (500 MHz, DMSO-d₆) δ 13.19(s, 1H), 9.11 (s, 1H), 9.09 (s, 1H), 3.47-2.90 (m, 5H), 2.71 (s, 3H),2.38 (s, 3H), 1.90-1.62 (m, 4H). 21

RT 4.05 min, MI 422, Method (1LCMS1); ¹H NMR (500 MHz, DMSO-d₆) δ 13.17(s, 1H), 9.16 (d, J = 2.0 Hz, 1H), 9.10 (s, 1H), 8.14 (d, J = 2.0 Hz,1H), 4.60 (s, 1H), 4.24 (d, 1H), 3.40 (d, 1H), 3.28-3.17 (m, 1H),3.00-2.88 (m, 1H), 2.69 (s, 3H), 1.96- 1.66 (m, 4H). 22

RT 4.12 min, MI 419, Method (1LCMS1); ¹H NMR (300 MHz, DMSO-d₆) δ 13.15(br s, 1H), 12.82 (br s, 1H), 9.09 (s, 1H), 6.27 (s, 1H), 4.81 (br s,1H), 4.60 (d, J = 12.7 Hz, 1H), 3.49-3.07 (m, 2H), 2.96-2.78 (m, 1H),2.68 (s, 3H), 2.23 (s, 3H), 1.90-1.57 (m, 4H). 23

RT 4.28 min, MI 433, Method (1LCMS1); ¹H NMR (500 MHz, DMSO-d₆) δ 13.17(s, 1H), 9.10 (s, 1H), 6.32 (s, 1H), 4.81 (d, J = 13.3 Hz, 1H), 4.60 (d,J = 12.9 Hz, 1H), 3.75 (s, 3H), 3.46-3.33 (m, 1H), 3.21 (t, J = 12.6 Hz,1H), 2.85 (t, J = 12.9 Hz, 1H), 2.69 (s, 3H), 2.26 (s, 3H), 1.89-1.61(m, 4H). 24

RT 4.38 min, MI 433, Method (1LCMS1); ¹H NMR (300 MHz, DMSO-d₆) δ 13.19(s, 1H), 9.11 (s, 1H), 6.20 (s, 1H), 4.57 (d, 1H), 3.95 (d, J = 13.1 Hz,1H), 3.74 (s, 3H), 3.49-3.18 (m, 2H), 3.05-2.86 (m, 1H), 2.70 (s, 3H),2.14 (s, 3H), 1.95-1.60 (m, 4H). 25

RT 4.51 min, MI 420, Method (1LCMS1). 26

RT 3.43 min, MI 417, Method (1LCMS1)

Synthesis of5-chloro-4-(1-isobutyl-4-piperidyl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one(27)

To a solution of5-chloro-2-(4-methylthiazol-5-yl)-4-(4-piperidyl)-1H-pyrimidin-6-one (2)(0.104 g, 0.300 mmol) in glacial acetic acid (10 mL) was addedisobutyraldehyde (0.435 mL, 4.800 mmol) and the mixture was left to stirat room temperature for 4 h. Sodium triacetoxyborohydride (0.318 g, 1.50mmol) was added and stirring continued for 18 h. After this time thereaction mixture was concentrated under vacuum and the residue waspartitioned between DCM and a saturated aqueous solution of NaHCO₃. TheDCM phase was dried (Na₂CO₃), filtered and concentrated under vacuum.The residue was purified by reverse phase column chromatography to givethe title compound (0.020 g, 18%). LCMS: RT 1.89 min, MI 367, Method(1LCMS1); ¹H NMR (300 MHz, DMSO-d₆+2 eq d-TFA) δ 13.56 (br s, 2H), 9.13(s, 1H), 3.59 (d, J=12.2 Hz, 2H), 3.42-3.25 (m, 1H), 3.17-3.00 (m, 2H),2.93 (d, J=7.2 Hz, 2H), 2.72 (s, 3H), 2.22-2.03 (m, 3H), 2.00-1.85 (m,2H), 0.96 (d, J=6.6 Hz, 6H).

General Scheme 2

In one approach (General Scheme 2), compounds of general formula [F2-3]were prepared by the reaction of an a-halo-malonate derivative ofgeneral formula [F2-1] in a condensation reaction utilising a suitablysubstituted heterocyclic carboximidamide derivative of general formula[F2-2] in a polar solvent such as methanol or THF in the presence of abase such as sodium methoxide, potassium tert-butoxide or DBU. Thereaction is suitably conducted at ambient temperature or at hightemperature either by heating thermally or using a microwave reactor.After reaction work up, typically by a liquid-liquid extraction, thereaction product was used crude in the next step or purified by flashcolumn chromatography, reverse phase preparative HPLC orre-crystallisation. Derivatives of general formula [F2-4] were preparedby the reaction of a 5-halo-2-heterocyclyl-1H-pyrimidine-4,6-dionederivative of general formula [F2-3] with a halogenating agent such asphosphorous oxychloride at high temperature. After reaction work up,typically by the addition of water followed by the addition of a basesuch as aqueous sodium hydroxide, the crude reaction mixture waspurified by liquid-liquid extraction, and the reaction product was usedcrude in the next step or purified by flash column chromatography,reverse phase preparative HPLC or re-crystallisation. Derivatives ofgeneral formula [F2-5] were prepared by a hydrolysis reaction of a4,5,6-halo-2-heterocyclyl-pyrimidine derivative of general formula[F2-4] with a mineral acid such as HCl or H₂SO₄ or an aqueous base suchas NaOH at high temperature. After reaction work up, typically by aliquid-liquid extraction, the reaction product was used crude in thenext step or purified by flash column chromatography, reverse phasepreparative HPLC or re-crystallisation. Compounds of general formula[F2-7] were prepared by reaction of5,6-dichloro-2-heterocyclyl-3H-pyrimidin-4-one derivatives of generalformula [F2-5] in a nucleophilic aromatic substitution type reactionutilising a suitable amine of general formula [F2-6], and a base such asEt₃N or NaH, or a mineral acid such as HCl, in a polar solvent such asethanol, butanol, dioxane, DMA or DMF at high temperature either byheating thermally or using a microwave reactor. After reaction work up,typically by a liquid-liquid extraction, the reaction product was usedcrude in the next step or purified by flash column chromatography,reverse phase preparative HPLC or re-crystallisation. In cases where theheterocycle (het) or substituent R′ or R″ contained an amine protectedby a standard amine protecting group such as a tert-butyloxycarbonyl(Boc), compounds of formula [F2-7] can be prepared by a suitabledeprotection reaction, for example reaction with an acid such as TFA ina suitable solvent such as DCM at ambient temperature. After reactionwork up, typically by a liquid-liquid extraction or purification byacidic ion exchange catch-release the crude product was purified byflash column chromatography, reverse phase preparative HPLC orre-crystallisation.

Synthesis of 5-chloro-2-(4-methylthiazol-5-yl)-1H-pyrimidine-4,6-dione(2-001)

To a solution of 4-methylthiazole-5-carboxamidine hydrochloride (1-001)(1.936 g, 10.90 mmol) in MeOH (50 mL) under nitrogen was added dimethylchloromalonate (1.53 mL, 11.99 mmol) followed by DBU (6.50 mL, 43.60mmol) (exotherm observed). The reaction mixture was then stirred at roomtemperature for 24 h under nitrogen before concentrating under vacuum.The oily residue was treated by the addition of 1 M aqueous HCl until pH2 was reached. The cream suspension was diluted with water (30 mL) thenfiltered through a sintered funnel and washed with 0.5 M aqueous HCl (30mL). The collected cream paste was taken into MeOH then sonicated for 40min. The suspension was collected by vacuum filtration then allowed todry by vacuum suction overnight to give the title compound (2.25 g, 85%)as a beige solid. LCMS: RT 2.70 min, MI 243, Method (1LCMS1).

Synthesis of 4-methyl-5-(4,5,6-trichloropyrimidin-2-yl)thiazole (2-002)

In a 50 mL round bottom flask under nitrogen,5-chloro-2-(4-methylthiazol-5-yl)-1H-pyrimidine-4,6-dione (2-001) (2.25g, 9.23 mmol) was added to POCl₃ (25 mL) and the reaction mixture washeated to 120° C. for 16 h before cooling to room temperature. Thereaction mixture was then carefully added to ice under vigorousstirring. The obtained suspension was filtered through a sinteredfunnel. The filtrate was extracted with DCM (×3) then neutralised andextracted with further DCM (×3). The combined organic phases wereconcentrated under vacuum to give the title compound (1.40 g, 54%) as abeige powder. LCMS: RT 6.37 min, MI 282, Method (1LCMS1).

Synthesis of 4,5-dichloro-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one(2-003)

In a 25 mL round bottom flask equipped with an air condenser,4-methyl-5-(4,5,6-trichloropyrimidin-2-yl)thiazole (2-002) (1.40 g, 5.00mmol) was added to concentrated HCl (25 mL) and the reaction mixture wasrefluxed for 4 days. The reaction mixture was then cooled to roomtemperature and the suspension was filtered through a sintered funnel.The collected solid was washed with water then dried by vacuumfiltration to give the title compound (1.18 g, 90%) as a beige powder.LCMS: RT 5.65 min, MI 262, Method (1 LCMS1).

Synthesis of5-chloro-2-(4-methylthiazol-5-yl)-4-[(3R)-3-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one(28)

To a solution of4,5-dichloro-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one (2-003) (0.100g, 0.382 mmol) in EtOH (2.5 mL) was added(2R)-2-(trifluoromethyl)piperazine (0.145 g, 0.763 mmol) followed byEt₃N (0.212 mL, 1.526 mmol). The mixture was heated in the microwave at150° C. for 45 min. The dark brown reaction mixture was allowed to coolto room temperature then sonicated for 15 min. The suspension wasconcentrated under vacuum, the residue taken into DMSO (2 mL) and heateduntil dissolution then allowed to crystallise. The suspension wasfiltered through a sintered funnel. The filtrate was purified bypreparative HPLC to give the title compound (0.095 g, 66%) as anoff-white powder. LCMS: RT 3.51 min, MI 378.3/380.3, Method (1LCMS1); ¹HNMR (300 MHz, DMSO-d₆) δ 9.07 (s, 1H), 4.18 (d, J=12.7 Hz, 1H), 3.98 (d,J=13.0 Hz, 1H), 3.61-3.46 (m, 1H), 3.24-3.06 (m, 2H), 3.00-2.92 (m, 1H),2.82-2.63 (m, 4H).

The following compounds were synthesised according to the generalsynthesis shown in scheme [2]:

No Product [F2-7] Characterisation 29

RT 3.72 min, MI 327/329, Method (1LCMS1); ¹H NMR (300 MHz, DMSO-d₆) δ12.41 (s, 1H), 9.06 (s, 1H), 4.75 (d, J = 4.1 Hz, 1H), 3.94 (dt, J =13.2, 4.2 Hz, 2H), 3.78-3.63 (m, 1H), 3.21 (ddd, J = 13.0, 9.7, 2.9 Hz,2H), 2.71 (s, 3H), 1.88-1.76 (m, 2H), 1.45 (dtd, J = 12.7, 9.2, 3.6 Hz,2H). 30

RT 5.72 min, MI 325/329, Method (1LCMS1); ¹H NMR (300 MHz, DMSO-d₆) δ9.03 (s, 1H), 4.16 (d, J = 13.0 Hz, 2H), 2.90 (t, J = 11.7 Hz, 2H), 2.71(s, 3H), 1.78- 1.47 (m, 3H), 1.33-1.07 (m, 2H), 0.91 (d, J = 6.3 Hz,3H). 31

RT 3.55 min, MI 380/382, Method (1LCMS1); ¹H NMR (300 MHz, DMSO-d₆) δ9.07 (s, 1H), 4.18 (d, J = 11.4 Hz, 1H), 3.98 (d, J = 13.0 Hz, 1H),3.62-3.44 (m, 1H), 3.23-3.06 (m, 2H), 3.02-2.90 (m, 1H), 2.80- 2.66 (m,4H). 32

RT 1.57 min, MI 326/328, Method (1LCMS1); ¹H NMR (300 MHz, DMSO-d₆) δ16.12 (br s, 2H), 9.12 (s, 1H), 4.17 (t, J = 13.3 Hz, 2H), 3.48-3.25 (m,3H), 3.21- 3.04 (m, 2H), 2.71 (s, 3H), 1.23 (d, J = 6.5 Hz, 3H). 33

RT 4.04 min, MI 341/343, Method (1LCMS1); ¹H NMR (500 MHz, methanol-d₄)δ 9.57 (s, 1H), 4.45 (d, J = 13.1 Hz, 2H), 3.46 (d, J = 6.2 Hz, 2H),3.03 (t, J = 12.7 Hz, 2H), 2.88 (s, 3H), 1.90-1.72 (m, 3H), 1.43-1.31(m, 2H). 34

RT 3.04 min, MI 340.0/341.9, Method (1LCMS1); ¹H NMR (300 MHz, DMSO-d₆)δ 12.19 (br s, 1H), 9.05 (s, 1H), 7.59 (t, J = 4.7 Hz, 1H), 4.30 (s,2H), 3.79 (t, J = 5.8 Hz, 2H), 3.23-3.06 (m, 2H), 2.69 (s, 3H), 2.05-1.87 (m, 2H). 35

RT 4.82 min, MI 347.0/348.9, Method (1LCMS1); ¹H NMR (300 MHz, DMSO-d₆)δ 8.93 (s, 1H), 3.72 (t, J = 11.9 Hz, 2H), 3.50-3.36 (m, 2H), 2.72 (s,3H), 2.17- 1.95 (m, 2H), 1.91-1.74 (m, 2H). 36

RT 4.29 min, MI 341.0/343.0, Method (1LCMS1); ¹H NMR (300 MHz, DMSO-d₆)δ 12.37 (s, 1H), 9.06 (s, 1H), 4.59-4.48 (m, 1H), 4.26 (d, J = 12.3 Hz,1H), 4.11 (d, J = 12.9 Hz, 1H), 3.39-3.18 (m, 2H), 2.95 (t, J = 11.0 Hz,1H), 2.80-2.65 (m, 4H), 1.80-1.61 (m, 3H), 1.61-1.41 (m, 1H), 1.30-1.08(m, 1H). 37

RT 1.41 min, MI 326.1/328.0, Method (1LCMS1); ¹H NMR (300 MHz, DMSO-d₆)δ 15.03 (br s, 2H), 9.11 (s, 1H), 4.17 (t, J = 13.4 Hz, 2H), 3.49-3.22(m, 3H), 3.22-3.02 (m, 2H), 2.70 (s, 3H), 1.23 (d, J = 6.5 Hz, 3H). 38

RT 1.04 min, MI 312.0/314.0, Method (2LCMS1) 39

RT 2.11 min, M: 354.1/356.1, Method (1LCMS1);

General Scheme 3

In one approach (General Scheme 3), compounds of general formula [F3-3]were prepared by the reaction of a 4,6-dichloro-5-halo-2-iodo-pyrimidinederivative of general formula [F3-1] in a nucleophilic aromaticsubstitution type reaction utilising a suitable amine of general formula[F3-2], and a base such as Et₃N or N,N-diisopropylethylamine in a polarsolvent such as ethanol, 1,4-dioxane, DMA or DMF at high temperatureeither by heating thermally or using a microwave reactor. After reactionwork up, typically by a liquid-liquid extraction, the reaction productwas used crude in the next step or purified by flash columnchromatography, reverse phase preparative HPLC or re-crystallisation.4-Chloro-5-halo-2-heterocyclyl-pyrimidine derivatives of general formula[F3-5] were prepared by a Suzuki-type coupling reaction with a suitableboronic acid or boronate ester of general formula [F3-4] utilising asuitable catalyst such as bis(triphenylphosphine)palladium(II)dichloride, tetrakis(triphenylphosphine)palladium, or1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a basesuch as sodium carbonate, potassium carbonate or cesium carbonate, in apolar solvent mixture such as 1,4-dioxane/water at high temperatureeither by heating thermally or using a microwave reactor. After reactionwork up, typically by a liquid-liquid extraction, the reaction productwas used crude in the next step or purified by flash columnchromatography, reverse phase preparative HPLC or re-crystallisation.5-Halo-(2-heterocyclyl)-3H-pyrimidin-4-one derivatives of generalformula [F3-6] were prepared by a hydrolysis reaction of4-chloro-5-halo-2-(heterocyclyl)-pyrimidine derivatives of generalformula [F3-5] with an aqueous base such as NaOH or KOH at hightemperature either by heating thermally or using a microwave reactor.After reaction work up, typically by a liquid-liquid extraction orpurification by acidic ion exchange catch-release the crude product waspurified by flash column chromatography, reverse phase preparative HPLCor re-crystallisation. In cases where the heterocycle (het) orsubstituent R′ or R″ contained an amine protected by a standard amineprotecting group such as tert-butyloxycarbonyl (Boc), compounds offormula [F3-6] are prepared by a suitable deprotection reaction, forexample reaction with an acid such as TFA or HCl in a suitable solventsuch as DCM at ambient temperature. After reaction work up, typically bya liquid-liquid extraction or purification by acidic ion exchangecatch-release the crude product was purified by flash columnchromatography, reverse phase preparative HPLC or re-crystallisation.

Synthesis of 4,5,6-trichloropyrimidin-2-amine (3-001)

A suspension of 2-amino-4,6-dichloropyrimidine (2.0 g, 12.20 mmol) inchloroform (30 mL) was prepared and N-chlorosuccinimide (1.71 g, 12.81mmol) was added portionwise. The reaction mixture was refluxed for 2 h.The reaction mixture was cooled to room temperature, diluted with asaturated solution of NaHCO₃ then extracted with DCM and ethyl acetate.A precipitate formed which was removed by filtration. The combinedorganic extracts were dried and concentrated under reduced pressure. Thecrude residue was purified by flash chromatography on silica gel,eluting with 0-40% EtOAc in cyclohexane. The appropriate fractions werecombined and concentrated to give the title compound (2.1 g, 86.8%yield). LCMS: RT 4.03 min, MI 199.8, Method (4LCMS1)

Synthesis of 4,5,6-trichloro-2-iodo-pyrimidine (3-002)

4,5,6-Trichloropyrimidin-2-amine (3-001) (5.0 g, 25.20 mmol) anddi-iodomethane (20.3 mL, 251.96 mmol) were suspended in MeCN (25 mL).This was then treated with the dropwise addition tert-butyl nitrite(15.04 mL, 125.98 mmol). The reaction turned pale green and a gas wasgiven off. The reaction mixture was heated to 80° C. for 2 hours beforeallowing to cool to room temperature and treating with saturated sodiumbicarbonate solution (gas evolved). The reaction was then extracted intoDCM (2×50 mL), the organics dried and concentrated under reducedpressure. The crude product was purified by flash chromatography onsilica gel, eluting with cyclohexane containing 0-5% EtOAc. Theappropriate fractions were combined and concentrated to give the titlecompound (4.13 g, 53% yield) as a white solid. LCMS: RT 4.98 min, MI310, Method (4LCMS1).

Synthesis of tert-butyl4-(5,6-dichloro-2-iodo-pyrimidin-4-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate(3-003)

To a solution of 4,5,6-trichloro-2-iodo-pyrimidine (3-002) (0.50 g, 1.62mmol) in 1,4-dioxane (5 mL) and N,N-diisopropylethylamine (0.56 mL, 3.23mmol) was added tert-butyl 6,6-difluoro-1,4-diazepane-1-carboxylate(0.42 g, 1.778 mmol) as a solution in 1,4-dioxane (5 mL) and thereaction was allowed to stir at room temperature overnight. The reactionwas concentrated and the residue was purified by column chromatographyeluting with an EtOAc/hexane gradient (10-30% EtOAc). Fractionscontaining the product were combined and concentrated under reducedpressure to give the title compound (500 mg, 60.8% yield) as acolourless oil. LCMS: RT 5.70 min, MI 508/510, Method (4LCMS1). ¹H NMR(400 MHz, DMSO-d₆) δ 4.68-4.01 (m, 2H), 4.08-3.49 (m, 6H), 1.41 (s, 9H).

Synthesis of 4-iodo-1-[(4-methoxyphenyl)methyl]pyrazole (3-004)

4-Iodopyrazole (10.0 g, 51.55 mmol) was dissolved in 1,4-dioxane (40 mL)and to this was added potassium carbonate (7.12 g, 51.55 mmol) followedby 4-methoxybenzyl chloride (6.99 mL, 51.55 mmol) and the reaction wasstirred at reflux overnight. Upon cooling, the reaction mixture wasconcentrated and the residue was partitioned between ethyl acetate andwater. The organic phase was washed with brine, dried over sodiumsulphate, filtered and evaporated to give a yellow oil. This waspurified by column chromatography eluting with an ethyl acetate/hexanegradient, 0-30% ethyl acetate. Fractions containing product werecombined and evaporated to give the title compound (9.20 g, 57%) as astraw coloured oil which crystallized on standing. ¹H NMR (400 MHz,DMSO-d₆) δ 7.98 (d, J=0.7 Hz, 1H), 7.52 (d, J=0.7 Hz, 1H), 7.28-7.17 (m,2H), 6.98-6.85 (m, 2H), 5.24 (s, 2H), 3.73 (s, 3H).

Synthesis of 5-chloro-4-iodo-1-[(4-methoxyphenyl)methyl]pyrazole (3-005)

A stirred solution of diisopropylamine (3.01 mL, 21.49 mmol) in THF (10mL) was prepared under nitrogen and cooled to −78° C. n-Butyllithium(2.5 M) in hexanes (8.28 mL, 20.69 mmol) was added and the reactionmixture warmed to 0° C. and stirred at this temperature for ten minutes.The reaction mixture was then cooled back to −78° C. This solution wasadded dropwise to a −78° C. solution of4-iodo-1-[(4-methoxyphenyl)methyl]pyrazole (3-004) (5.00 g, 15.92 mmol)in tetrahydrofuran (10 mL) over two minutes. After five minutes,hexachloroethane (4.52 g, 19.10 mmol) diluted in the minimum amount ofTHF was added and stirring was continued at −78° C. for 1 h. Thesolution was then allowed to warm to room temperature. Saturated aqueousammonium chloride was added and the mixture was extracted with ethylacetate (2×50 mL). The organic layers were combined, dried over sodiumsulphate, filtered and evaporated. The resulting residue was purified byflash chromatography on silica gel eluting with tert-butylmethylether/petroleum ether gradient, 0-20% TBME. Fractions containing productwere combined and evaporated to give the title compound (4.40 g, 79%) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.71 (s, 1H), 7.16 (d, J=8.6Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 5.35 (s, 2H), 3.73 (s, 3H).

Synthesis of5-chloro-1-[(4-methoxyphenyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole(3-006)

5-Chloro-4-iodo-1-[(4-methoxyphenyl)methyl]pyrazole (3-005) (5.30 g,15.20 mmol) was dissolved in acetonitrile (4 mL) and to this was addedpalladium acetate (68.27 mg, 0.304 mmol), copper (I) iodide (0.579 g,3.04 mmol), triphenylphosphine (79.76 mg, 0.304 mmol), cesium carbonate(7.431 g, 22.81 mmol) and bis(pinacolato)diboron (5.79 g, 22.81 mmol)and the reaction was stirred at room temperature overnight. To thereaction was added a further portion of copper (I) iodide (0.579 g, 3.04mmol), triphenylphosphine (79.76 mg, 0.304 mmol), palladium acetate(68.27 mg, 0.304 mmol) and the reaction was stirred at room temperaturefor 5 h. The reaction was concentrated and the residue was purified bycolumn chromatography using an ethyl acetate/petroleum ether gradienteluting with 0-20% ethyl acetate. Fractions containing product werecombined and concentrated to give the title compound (3.00 g, 57%) as acolourless oil which crystallized on standing. LCMS: RT 5.06 min, MI348, Method (4LCMS3); ¹H NMR (400 MHz, DMSO-d₆) δ 7.70 (s, 1H), 7.15 (d,J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 5.30 (s, 2H), 3.73 (s, 3H), 1.16(s, 12H).

Synthesis of tert-butyl4-[5,6-dichloro-2-[5-chloro-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]pyrimidin-4-yl]-6,6-difluoro-1,4-diazepane-1-carboxylate(3-007)

tert-Butyl4-(5,6-dichloro-2-iodo-pyrimidin-4-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate(3-003) (0.250 g, 0.491 mmol),5-chloro-1-[(4-methoxyphenyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole(3-006) (0.21 g, 0.589 mmol),1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (0.04 g, 0.049 mmol), and sodium hydrogen carbonate(0.080 g, 0.982 mmol), were treated with 1,4-dioxane (5 mL) and water (1mL) and heated to 100° C. overnight. This was then diluted with water(100 mL) which was then extracted into DCM (2×100 mL) and EtOAc (100mL). The organic fractions were combined and evaporated. The residue waspurified by flash chromatography on silica gel (eluting with 0-20% ethylacetate in cyclohexane). The fractions containing the product werecombined and evaporated to give the title compound (110 mg, 37%). LCMS:RT 6.20 min, MI 605, Method (4LCMS1).

Synthesis of tert-butyl4-[5-chloro-2-[5-chloro-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]-6-oxo-1H-pyrimidin-4-yl]-6,6-difluoro-1,4-diazepane-1-carboxylate(3-008)

tert-Butyl4-[5,6-dichloro-2-[5-chloro-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]pyrimidin-4-yl]-6,6-difluoro-1,4-diazepane-1-carboxylate(3-007) (0.110 g, 0.182 mmol) was dissolved in 1,4-dioxane (2 mL) andtreated with 2 M aqueous NaOH (1.09 mL, 2.19 mmol). This was then heatedin the microwave to 120° C. for 60 minutes. The reaction mixture wasthen diluted by the addition of DCM and washed with water. The DCM layerwas evaporated and the residue purified by flash chromatography onsilica gel (eluting with 0-100% ethyl acetate in cyclohexane followed by0-10% methanol in DCM). The fractions containing the product werecombined and evaporated to give the title compound (45 mg, 42%). LCMS:RT 4.95 min, MI 585, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 12.63(s, 1H), 8.39 (s, 1H), 7.22 (d, J=8.7 Hz, 2H), 6.99-6.85 (m, 2H), 5.37(s, 2H), 4.38 (t, J=12.6 Hz, 2H), 3.80 (d, J=14.3 Hz, 6H), 3.73 (s, 3H),1.39 (d, J=12.5 Hz, 9H).

Synthesis of5-chloro-2-(5-chloro-1H-pyrazol-4-yl)-4-(6,6-difluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-onehydrochloride (40)

tert-Butyl4-[5-chloro-2-[5-chloro-1-[(4-methoxyphenyl)methyl]pyrazol-4-yl]-6-oxo-1H-pyrimidin-4-yl]-6,6-difluoro-1,4-diazepane-1-carboxylate(3-008) (0.050 g, 0.077 mmol) was dissolved in TFA (1.00 mL, 0.077 mmol)and DCM (1 mL) and left to stir at room temperature for 4 hours, then80° C. for 2 hours. The reaction mixture was then allowed to return toroom temperature and evaporated to dryness. The residue was treated with2 M HCl in diethyl ether (1 mL), the reaction was filtered and washedwith ether. The solid was then dissolved in DMSO and purified bypreparative HPLC. The fractions recovered were then treated with 2 M HClin diethyl ether (1 mL) and evaporated to give the title compound (12mg, 39%). LCMS: RT 1.74 min, MI 365, Method (4LCMS1); ¹H NMR (400 MHz,DMSO-d₆) δ 13.71 (s, 1H), 12.61 (s, 1H), 8.64 (s, 1H), 4.60 (t, J=13.3Hz, 2H), 4.01 (d, J=5.5 Hz, 2H), 3.76 (t, J=12.9 Hz, 2H), 3.56-3.42 (m,2H).

Synthesis of(3R)-4-(5,6-dichloro-2-iodo-pyrimidin-4-yl)-3-methyl-morpholine (3-009)

To a stirred solution of 4,5,6-trichloro-2-iodo-pyrimidine (3-002) (2.00g, 6.47 mmol) and triethylamine (0.950 mL, 6.79 mmol) in chloroform (60mL) was added (R)-3-methylmorpholine (0.730 mL, 6.47 mmol). The reactionmixture was stirred at room temperature under nitrogen for 100 h. Water(30 mL) was added and the two phases were separated. The aqueous wasfurther extracted with DCM (2×15 mL). The combined organics were dried(phase separator) and concentrated to a yellow oil. The oil was purifiedusing flash chromatography on silica gel eluting with a mixture of ethylacetate in petroleum ether (0-50%). Desired fractions were concentratedaffording the title compound (1.53 g, 63%) as a white powder. LCMS: 5.25min, MI 374, method (4LCMS1); ¹H NMR (400 MHz, CDCl₃) δ 4.55 (qd, J=6.9,3.0 Hz, 1H), 4.17-4.07 (m, 1H), 3.94 (ddd, J=11.3, 3.4, 1.4 Hz, 1H),3.71 (d, J=2.2 Hz, 2H), 3.62 (td, J=11.7, 2.5 Hz, 1H), 3.54-3.43 (m,1H), 1.43 (d, J=6.8 Hz, 3H).

Synthesis of(3R)-4-[5,6-dichloro-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]pyrimidin-4-yl]-3-methyl-morpholine(3-010)

(3R)-4-(5,6-dichloro-2-iodo-pyrimidin-4-yl)-3-methyl-morpholine (3-009)(0.630 g, 1.68 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole(0.440 g, 1.68 mmol),1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (0.140 g, 0.168 mmol), and sodium hydrogen carbonate(0.280 g, 3.37 mmol) were treated with 1,4-dioxane (1.5 mL) and water(0.5 mL) and heated to 120° C. in the microwave for 20 minutes. This wasthen diluted with DCM (20 mL) and washed with water (20 mL). The DCM wasthen evaporated and purified by flash chromatography on silica gel(eluting with 0-50% ethyl acetate in cyclohexane). The fractionscontaining the product were combined and evaporated to give the titlecompound (0.550 g, 85%). LCMS: RT 4.93 min, MI 382, Method (4LCMS1); ¹HNMR (400 MHz, DMSO-d₆) (13.99 (s, 1H), 8.74-8.39 (m, 1H), 4.50 (d, J=7.3Hz, 1H), 4.14-4.04 (m, 1H), 3.89 (d, J=11.2 Hz, 1H), 3.71-3.40 (m, 3H),1.40 (s, 1H), 1.36 (d, J=6.8 Hz, 3H).

Synthesis of5-chloro-4-[(3R)-3-methylmorpholin-4-yl]-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one(41)

(3R)-4-[5,6-dichloro-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]pyrimidin-4-yl]-3-methyl-morpholine(3-010) (0.550 g, 1.44 mmol) was treated with 1,4-dioxane (8.6 mL) and 2M aqueous sodium hydroxide (8.63 mL, 17.27 mmol) and heated to 100° C.for 3 days. The reaction mixture was cooled to room temperatureovernight then cooled to 5° C. in an ice bath and treated with saturatedsodium citrate (10 mL), a white precipitate was formed. The mixture wastreated with ethyl acetate (75 mL) and water (25 mL) and gently mixed.The layers were separated and the aqueous was extracted with furtherethyl acetate (75 mL). The organic layers were combined, washed withwater (50 mL) then brine (50 mL), and passed through a phase separatorand the filtrate evaporated. The residue was purified by flashchromatography on silica gel, eluting with 0-100% ethyl acetate then0-10% methanol in DCM. The appropriate fractions were combined andconcentrated under reduced pressure to give a pale yellow solid. Thesolid was suspended in diethyl ether, filtered, washed with more etherand dried overnight in a vacuum oven. The solid was then suspended inmethanol and concentrated. The residue was suspended in water and thenconcentrated. The residue was purified by SCX, washing first withmethanol then with 2 M methanolic ammonia. The first fraction eluted wasevaporated to give the title compound (0.029 g, 6%) as a yellow powder.LCMS: RT 3.45 min, MI 364, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ14.09 (s, 1H), 12.57 (s, 1H), 8.70 (s, 1H), 4.37 (d, J=7.3 Hz, 1H), 3.86(t, J=12.4 Hz, 2H), 3.70-3.35 (m, 4H), 1.30 (d, J=6.8 Hz, 3H).

Synthesis of1-[(4-methoxyphenyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyrazole(3-011)

Potassium carbonate (678.8 g, 4911 mmol) was added to a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole(2.00 g, 7.63 mmol) in MeCN (30 mL) followed by 4-methoxybenzyl chloride(1.03 mL, 7.63 mmol) and the reaction mixture was refluxed overnight.The mixture was concentrated under reduced pressure and the residuediluted with brine and EtOAc. The aqueous phase was extracted withEtOAc. The organic solvent was dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel, eluting with 0-30% EtOAC:cyclohexane.Fractions containing product were combined and evaporated to give thetitle compound (2.27 g, 78%) as a mixture of pyrazole isomers. LCMS: RT3.46/3.59 min, MI 383, Method (1 LCMS13).

The following compounds were synthesised according to the generalsynthesis shown in scheme [3]:

No [F3-4] Product [F3-6] Characterisation 42

RT 3.09 min, MI 329/331, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ13.62 (s, 1H), 12.39 (s, 1H), 8.60 (s, 1H), 4.46 (d, J = 7.1 Hz, 1H),4.20-3.93 (m, 1H), 3.93-3.76 (m, 1H), 3.69-3.58 (m, 2H), 3.53 (td, J =11.4, 2.6 Hz, 1H), 3.38 (m 1H), 1.33 (d, J = 6.8 Hz, 3H). 43

RT 1.68 min, MI 329, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 13.72(s, 1H), 12.58 (s, 1H), 9.67-9.20 (m, 1H), 9.02 (s, 1H), 8.63 (s, 1H),4.60 (dd, J = 7.3, 3.8 Hz, 1H), 4.14 (d, J = 14.7 Hz, 1H), 3.43 (ddd, J= 14.6, 11.7, 2.8 Hz, 1H), 3.27 (d, J = 12.5 Hz, 1H), 3.17 (s, 3H), 1.43(d, J = 7.0 Hz, 3H). 44

RT 1.79 min, MI 363, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 14.21(s, 1H), 12.77 (s, 1H), 9.41 (s, 1H), 9.02 (s, 1H), 8.73 (s, 1H), 4.54(dt, J = 7.0, 3.4 Hz, 1H), 4.04- 3.92 (m, 1H), 3.49-3.39 (m, 1H), 3.21(d, J = 27.1 Hz, 3H), 2.99 (d, J = 10.8 Hz, 1H), 1.39 (d, J = 7.0 Hz,3H). 45

RT 2.49 min, MI 399/401, Method (2LCMS5) 46

RT 2.02 min, MI 377/378, Method (1LCMS12) 47

RT 3.23 min, MI 350/351, Method (1LCMS12); ¹H NMR (600 MHz, DMSO-d₆) δ8.70 (s, 1H), 3.68-3.64 (m, 4H), 3.63-3.58 (m, 4H). 48

RT 1.65 min, MI 309/310, Method (1LCMS12); ¹H NMR (600 MHz, Methanol-d₄)δ 8.03 (s, 1H), 4.02 (dq, J = 10.0, 6.2, 5.8 Hz, 1H), 3.37- 3.32 (m,1H), 3.27-3.20 (m, 1H), 3.02 (dd, J = 12.5, 3.7 Hz, 1H), 2.97-2.87 (m,2H), 2.67 (dd, J = 12.6, 5.3 Hz, 1H), 2.60 (s, 3H), 1.16 (d, J = 6.5 Hz,3H). 49

RT 1.65 min, MI 310/312, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d6) δ12.90 (s, 1H), 9.56 (s, 1H), 9.53-9.43 (m, 1H), 9.12 (s, 1H), 4.60-4.47(m, 1H), 4.01 (dd, J = 14.6, 3.2 Hz, 1H), 3.49-3.39 (m, 1H), 3.31-3.24(m, 1H), 3.22-3.12 (m, 2H), 3.12-2.97 (m, 1H), 1.40 (d, J = 7.0 Hz, 3H).50

RT 1.57 min, MI 309, Method (4LCMS1). ¹H NMR (400 MHz, DMSO-d₆) δ 12.85(s, 1H), 9.36 (s, 1H), 9.00 (s, 1H), 7.57 (s, 1H), 7.19 (s, 1H), 4.54(d, J = 7.1 Hz, 1H), 4.15 (s, 3H), 4.04- 3.93 (m, 1H), 3.45 (ddd, J =14.6, 11.7, 2.9 Hz, 1H), 3.31-3.24 (m, 1H), 3.19 (d, J = 3.4 Hz, 2H),3.06 (t, J = 11.8 Hz, 1H), 1.40 (d, J = 7.0 Hz, 3H). 51

RT 2.66 min, MI 296/298, Method (1LCMS12) 52

RT 1.72 min, MI 381, Method (1LCMS13); ¹H NMR (600 MHz, DMSO-d₆) δ 12.56(s, 2H), 8.61 (s, 1H), 8.51 (d, J = 7.9 Hz, 1H), 8.36 (d, J = 4.7 Hz,1H), 7.29 (dd, J = 8.0, 4.7 Hz, 1H), 4.56 (t, J = 13.3 Hz, 2H), 3.99 (s,2H), 3.63 (t, J = 13.1 Hz, 2H), 3.45 (s, 2H). 53

RT 2.26 min, MI 346, Method (1LCMS13); ¹H NMR (600 MHz, DMSO-d₆) δ 12.49(br s, 1H), 12.44 (br s, 1H), 8.61 (br d, J = 2.4 Hz, 1H), 8.57 (d, J =7.4 Hz, 1H), 8.34 (dd, J = 4.5, 1.4 Hz, 1H), 7.27 (dd, J = 7.9, 4.6 Hz,1H), 4.41- 4.40 (m, 1H), 3.95-3.93 (m, 1H), 8.83 (d, J = 13.2 Hz, 1H),3.71-3.65 (m, 2H), 3.62-3.58 (m, 1H), 3.53-3.48 (m, 1H), 1.32 (d, J =6.7 Hz, 3H). 54

RT 3.39 min, MI 346.12, Method (1LCMS12); ¹H NMR (600 MHz,Methanol-d₄/CDCl₃) δ 8.67 (s, 1H), 8.64 (d, J = 6.7 Hz, 1H), 8.39 (d, J= 9.0 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.22 (t, J = 6.9 Hz, 1H), 4.56(q, J = 6.2 Hz, 1H), 4.04-3.97 (m, 2H), 3.83 (dd, J = 3.0 and 11.3 Hz,1H), 3.77- 3.70 (m, 2H), 3.63 (ddd, J = 3.2, 11.4 and 14.0 Hz, 1H), 1.44(d, J = 6.8 Hz, 3H).

Synthesis of tert-butyl(3R)-4-(5,6-dichloro-2-iodo-pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate(3-012)

To a stirred solution of 4,5,6-trichloro-2-iodo-pyrimidine (3-002) (18.8g, 60.8 mmol) and triethylamine (8.9 mL, 63.9 mmol) in chloroform (160mL) was added (R)-1-boc-3-methylpiperazine (12.2 g, 60.8 mmol). Thereaction was stirred at room temperature under nitrogen for 20 h. Water(100 mL) was added and the two phases were separated. The aqueous wasextracted with DCM (2×100 mL). The combined organics were dried andconcentrated affording a yellow oil. The oil was dissolved into a smallamount of warm methanol. The mixture cooled causing a white precipitateto form. The precipitate was collected via vacuum filtration and driedunder vacuum affording the title compound (19 g, 66%) as a white powder.LCMS: RT 5.98 min, MI 473, method (4LCMS1); ¹H NMR (400 MHz, CDCl₃) δ4.61 (s, 1H), 4.25-3.80 (m, 3H), 3.34 (dd, J=13.8, 3.5 Hz, 1H),3.18-2.89 (m, 2H), 1.48 (s, 9H), 1.32 (d, J=6.7 Hz, 3H).

Synthesis of tert-butyl(3R)-4-(5-chloro-2-iodo-6-oxo-1H-pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate(3-013)

A suspension of tert-butyl(3R)-4-(5,6-dichloro-2-iodo-pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate(3-012) (0.200 g, 0.423 mmol) in 1,4-dioxane (3 mL) was prepared andNaOH (3.17 mL of a 2M aq solution, 6.34 mmol) was added. The reactionmixture was stirred at room temperature for 1 h, then heated to 100° C.for 1 h. The reaction mixture was cooled to room temperature andneutralised to pH 7 by addition of a saturated aqueous solution of NH₄Clthen HCl (1 M aq). The mixture was extracted with CH₂Cl₂ (2×25 mL) then9:1 CHCl₃:iso-propanol (20 mL). The combined organic extracts were driedover MgSO₄, filtered and concentrated by rotary evaporation. The residuewas purified by column chromatography on silica gel, eluting with 50-75%EtOAc in cyclohexane. The appropriate fractions were combined andconcentrated to give the title compound (0.107 g, 56%). LCMS RT 2.88min, MI 455, Method (1LCMS13).

Synthesis of tert-butyl(3R)-4-[2-[1-(benzenesulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-chloro-6-oxo-1H-pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(3-014)

A suspension of tert-butyl(3R)-4-(5-chloro-2-iodo-6-oxo-1H-pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate(3-013) (0.100 g, 0.220 mmol), 1-(phenylsulfonyl)-7-azaindole-3-boronicacid pinacol ester (0.089 g, 0.231 mmol), cesium carbonate (0.107 g,0.330 mmol) and tetrakis(triphenylphosphine)palladium (0.013 g, 0.011mmol) in 1,4-dioxane (1 mL) and water (0.3 mL) was prepared, degassed,and heated to 80° C. for 1 h. The reaction mixture was partitionedbetween NaHCO₃ (sat. aq) and CH₂Cl₂. The organic phase was separated andthe aqueous extracted with CH₂Cl₂. The combined organic portions weredried over MgSO₄, filtered and concentrated by rotary evaporation. Theresidue was purified by column chromatography on silica gel, elutingwith cyclohexane containing 5-50% EtOAc. The appropriate fractions werecombined and concentrated to the title compound (0.050 g, 39%) as acolourless solid. LCMS: RT 3.33 min, MI 585, Method (1LCMS13); ¹H NMR(600 MHz, DMSO-d₆) δ 12.82 (s, 1H), 9.15 (s, 1H), 8.60 (d, J=7.9 Hz,1H), 8.47 (dd, J=4.9, 1.6 Hz, 1H), 8.16-8.15 (m, 2H), 7.78-7.75 (m, 1H),7.66 (t, J=7.9 Hz, 2H), 7.50 (dd, J=8.0, 4.8 Hz, 1H), 4.47 (br s, 1H),4.04-3.99 (m, 2H), 3.78 (dt, J=13.2, 2.1 Hz, 1H), 3.35-3.30 (m, 1H),3.20-2.95 (br m, 2H), 1.41 (s, 9H), 1.21 (d, J=6.7 Hz, 3H).

Synthesis of tert-butyl(3R)-4-[5-chloro-6-oxo-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(3-015)

A suspension of tert-butyl(3R)-4-[2-[1-(benzenesulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-chloro-6-oxo-1H-pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(3-014) (0.050 g, 0.085 mmol) in 1,4-dioxane (1 mL) was prepared andsodium tert-butoxide (0.012 g, 0.128 mmol) was added. The mixture washeated to 80° C. for 1 h then cooled to room temperature, diluted withwater and extracted with CHCl₃:iso-propanol. The combined organicportions were dried over MgSO₄, filtered and concentrated by rotaryevaporation. The residue was purified by column chromatography on silicagel, eluting with dichloromethane containing 0-10% MeOH, then 10-20%MeOH. The appropriate fractions were combined and concentrated to givethe title compound (0.012 g, 32%). LCMS: RT 2.73 min, MI 445, Method(1LCMS13). ¹H NMR (600 MHz, DMSO-d₆) δ 12.48 (br s, 1H), 12.42 (br s,1H), 8.61-8.58 (m, 2H), 8.34 (dd, J=4.7, 1.6 Hz, 1H), 7.30 (dd, J=8.0,4.6 Hz, 1H), 4.50 (br s, 1H), 4.06-3.93 (m, 2H), 3.79 (d, J=13.2 Hz,1H), 3.37-3.34 (br m, 1H), 3.21-3.00 (m, 2H), 1.43 (s, 9H), 1.24 (d,J=6.9 Hz, 3H).

Synthesis of5-chloro-4-[(2R)-2-methylpiperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-6-one2,2,2-trifluoroacetic acid (55)

A solution of tert-butyl(3R)-4-[5-chloro-6-oxo-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(0.027 g, 0.0607 mmol) (3-015) in chloroform (0.500 mL) was prepared andtrifluoroacetic acid (0.093 mL, 1.21 mmol) was added. The reactionmixture was stirred at room temperature for 3 h. The reaction mixturewas concentrated by rotary evaporation and the residue was triturated indiethyl ether. The resulting yellow solid was filtered and dried undervacuum to give the title compound (0.008 g, 29%). LCMS: RT 1.66 min, MI345, Method (1LCMS13); ¹H NMR (500 MHz, DMSO-d₆) δ 12.59 (s, 1H), 12.54(s, 1H), 8.82 (br d, J=141.6 Hz, 2H), 8.64 (d, J=3.1 Hz, 1H), 8.54 (dd,J=8.1, 1.5 Hz, 1H), 8.36 (dd, J=4.7, 1.7 Hz, 1H), 7.27 (dd, J=8.0, 4.7Hz, 1H), 4.60-4.52 (m, 1H), 4.05-3.98 (m, 1H), 3.54-3.46 (m, 1H),3.39-3.36 (m, 1H), 3.29-3.13 (m, 3H), 1.39 (d, J=6.9 Hz, 3H).

Synthesis of(3R)-4-[5,6-dichloro-2-(2-methylimidazol-1-yl)pyrimidin-4-yl]-3-methyl-morpholine(3-016)

To a thoroughly degassed solution of(3R)-4-(5,6-dichloro-2-iodo-pyrimidin-4-yl)-3-methyl-morpholine (200 mg,0.535 mmol) (3-009), 2-methylimidazole (43.9 mg, 0.535 mmol), potassiumcarbonate (81.3 mg, 0.588 mmol) and 8-hydroxyquinoline (3.88 mg, 0.027mmol) in DMSO (5 mL) was added copper iodide (5.09 mg, 0.027 mmol). Themixture was heated to 110° C. for 2 h. The mixture was then cooled toroom temperature and diluted with water (50 mL) causing a blueprecipitate to form. The mixture was filtered and the filter cake waswashed with ethyl acetate (2×20 mL). The filtrate was separated with theaqueous being further extracted with ethyl acetate (3×20 mL), thecombined organics were concentrated to dryness to afford a green oil.The oil was purified using flash chromatography on C18 silica geleluting with a mixture of acetonitrile in water (5-40% with 0.1% formicacid). The desired fractions were passed through an SCX-2 cartridge andthe product was eluted with ammonia in methanol. The basic eluent wasconcentrated to dryness to afford the title compound (126 mg, 72%) as ayellow green film. LCMS: 2.51 min, MI 328, Method (4LCMS1); ¹H NMR (400MHz, CDCl₃) δ 7.72 (d, J=1.7 Hz, 1H), 6.93 (d, J=1.7 Hz, 1H), 4.57 (d,J=7.0 Hz, 1H), 4.10 (dt, J=13.5, 1.2 Hz, 1H), 4.01-3.96 (m, 1H), 3.76(d, J=2.2 Hz, 2H), 3.68 (td, J=11.5, 2.4 Hz, 1H), 3.60-3.51 (m, 1H),2.77 (s, 3H), 1.46 (d, J=6.8 Hz, 3H).

Synthesis of5-chloro-2-(2-methylimidazol-1-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyrimidin-6-one(56)

To a vial containing(3R)-4-[5,6-dichloro-2-(2-methylimidazol-1-yl)pyrimidin-4-yl]-3-methyl-morpholine(3-016) (126 mg, 0.384 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL)was added sodium hydroxide (0.18 g, 4.61 mmol). The vial was sealed andirradiated in the microwave to 120° C. for 20 min. 1 M aqueous HCl wasadded to bring the mixture to pH 7 before being passed through an SCX-2cartridge. The cartridge was washed with methanol before the compoundwas eluted with 2.0 M ammonia in methanol. The basic fraction wasconcentrated to dryness to afford a white film. The film was purified byflash chromatography on C18 silica gel eluting with a mixture ofacetonitrile in water (5-100% with 0.1% formic acid). The desiredfractions were concentrated to dryness to afford the title compound(5.43 mg, 5%) as a white powder. LCMS: 2.21 min, MI 310, Method(4LCMS1); ¹H NMR (400 MHz, Methanol-d₄) δ 7.89 (d, J=1.9 Hz, 1H), 7.03(d, J=1.8 Hz, 1H), 4.37-4.30 (m, 1H), 3.89 (dt, J=11.3, 3.0 Hz, 1H),3.79 (dd, J=11.3, 3.1 Hz, 1H), 3.70 (td, J=10.9, 2.8 Hz, 1H), 3.64 (dd,J=11.2, 2.7 Hz, 2H), 3.55-3.46 (m, 1H), 2.82 (s, 3H), 1.29 (d, J=6.7 Hz,3H).

General Scheme 4.

In one approach (General Scheme 4), compounds of general formula [F4-3]were prepared by the reaction of a 4,6-dichloro-5-halo-2-iodo-pyrimidinederivative of general formula [F4-1] in a nucleophilic aromaticsubstitution type reaction utilising a suitable amine of general formula[F4-2], and a base such as Et₃N or N,N-diisopropylethylamine in a polarsolvent such as ethanol, 1,4-dioxane, DMA or DMF at high temperatureeither by heating thermally or using a microwave reactor. After reactionwork up, typically by a liquid-liquid extraction, the reaction productwas used crude in the next step or purified by flash columnchromatography, reverse phase preparative HPLC or re-crystallisation.5-Halo-(2-heterocyclyl)-3H-pyrimidin-4-one derivatives of generalformula [F4-5] were prepared by a metal catalysed C—H activationcoupling reaction of compounds of general formula [F4-3] with a suitableheterocycle of general formula [F4-4] utilising a suitable catalyst suchas palladium acetate and a base such as cesium carbonate, with orwithout a suitable ligand such as tri-tert-butylphosphoniumtetrafluoroborate, in a polar solvent such as tert-butanol,iso-amylalcohol or DMA at high temperature either by heating thermallyor using a microwave reactor. After reaction work up, typically by aliquid-liquid extraction, the reaction product was used crude in thenext step or purified by flash column chromatography, reverse phasepreparative HPLC or re-crystallisation. In cases where the heterocycle(het) or substituent R′ or R″ contained an amine protected by a standardamine protecting group such as tert-butyloxycarbonyl (Boc), compounds offormula [F4-5] are prepared by a suitable deprotection reaction, forexample reaction with an acid such as TFA or HCl in a suitable solventsuch as DCM at ambient temperature. After reaction work up, typically bya liquid-liquid extraction or purification by acidic ion exchangecatch-release the crude product was purified by flash columnchromatography, reverse phase preparative HPLC or re-crystallisation.

Synthesis of tert-butyl4-[5-chloro-2-(4-methylthiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-6,6-difluoro-1,4-diazepane-1-carboxylate(4-001)

A stirred solution of 4-methylthiazole (0.15 mL, 1.62 mmol), tert-butyl4-(5,6-dichloro-2-iodo-pyrimidin-4-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate(3-003, prepared in scheme 3) (0.75 g, 1.47 mmol) and cesium carbonate(1.44 g, 4.42 mmol) in DMA (10 mL) was degassed and placed under anitrogen atmosphere. Palladium acetate (0.03 g, 0.147 mmol) was addedand the mixture was heated to 110° C. for 18 h. The reaction mixture wasconcentrated, affording a black oil. The oil was purified using flashchromatography on silica gel eluting with a mixture of ethyl acetate inDCM (20-100%). The desired fractions were concentrated to drynessaffording the title compound (0.254 g, 37%) as a yellow film. LCMS: 4.17min, MI 462, method (4LCMS1); ¹H NMR (400 MHz, CDCl₃) δ 12.57 (s, 1H),8.85 (s, 1H), 4.34 (t, J=12.2 Hz, 2H), 3.86 (d, J=12.4 Hz, 6H), 2.80 (s,3H), 1.49 (s, 9H).

Synthesis of5-chloro-4-(6,6-difluoro-1,4-diazepan-1-yl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-onehydrochloride (57)

To a stirred solution of tert-butyl4-[5-chloro-2-(4-methylthiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-6,6-difluoro-1,4-diazepane-1-carboxylate(4-001) (0.25 g, 0.55 mmol) in DCM (5 mL) was added HCl (2.75 mL of a2.0 M solution in diethyl ether, 5.49 mmol) under nitrogen. The reactionwas allowed to stir for 18 h. After this time, a yellow precipitateformed in the reaction which was collected via vacuum filtration. Theresulting powder was purified using basic preparative LCMS. The desiredfractions were concentrated affording a white powder. The powder wasdissolved in DCM and 2.0 M hydrogen chloride in diethyl ether was addedcausing precipitation of a yellow powder. The powder was collected viavacuum filtration to give the title compound (160 mg, 73%) as a yellowpowder. LCMS: 1.93 min, MI 362, Method (2LCMS1); ¹H NMR (400 MHz,Methanol-d₄) δ 9.50 (s, 1H), 4.56 (t, J=13.5 Hz, 2H), 4.17 (t, J=5.4 Hz,2H), 3.89 (t, J=11.9 Hz, 2H), 3.68 (t, J=5.4 Hz, 2H), 2.87 (s, 3H).

The following compounds were synthesised according to the generalsynthesis shown in scheme [4]:

Number Product [F4-5] Characterisation 58

RT 1.64 min, MI 326, Method (4LCMS1); ¹H NMR (400 MHz, Methanol-d₄) δ9.70 (s, 1H), 4.80-4.66 (m, 1H), 4.17 (dt, J = 14.9, 2.9 Hz, 1H), 3.63(td, J = 14.8, 3.0 Hz, 1H), 3.47-3.23 (m, 4H), 2.92 (s, 3H), 1.48 (d, J= 7.0 Hz, 3H). 59

RT 3.17 min, MI 327; Method (4LCMS1); ¹H NMR (400 MHz, Methanol-d₄) δ8.98 (s, 1H), 4.51-4.45 (m, 1H), 4.04-3.84 (m, 2H), 3.81-3.49 (m, 4H),2.75 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H). 60

RT 1.89 min, MI 380, Method (2LCMS1); ¹H NMR (400 MHz, Methanol-d₄) δ9.18 (s, 1H), 5.62-5.43 (m, 1H), 4.28 (d, J = 15.0 Hz, 1H), 3.89 (d, J =14.3 Hz, 1H), 3.78 (t, J = 13.9 Hz, 1H), 3.64 (dd, J = 14.3, 6.0 Hz,1H), 3.55-3.42 (m, 1H), 3.39-3.20 (m, 1H), 2.80 (s, 3H). 61

RT 1.71 min, MI 362, Method (2LCMS1); ¹H NMR (400 MHz, Methanol-d₄) δ9.37 (s, 1H), 6.48 (td, J = 53.7, 2.2 Hz, 1H), 4.36 (d, J = 15.1 Hz,1H), 3.80 (d, J = 13.9 Hz, 1H), 3.72 (t, J = 13.9 Hz, 1H), 3.54- 3.42(m, 3H), 3.41-3.31 (m, 1H), 2.84 (s, 3H). 62

RT 1.74 min, MI 344, Method (2LCMS1); ¹H NMR (400 MHz, Methanol-d₄) δ9.12 (s, 1H), 5.35 (dd, J = 44.3, 4.6 Hz, 1H), 4.63-4.42 (m, 1H), 4.32-3.95 (m, 3H), 3.85-3.76 (m, 1H), 3.74-3.65 (m, 1H), 3.64-3.50 (m, 1H),3.30-3.23 (m, 1H), 2.77 (s, 3H). 63

RT 2.03 min, MI 416, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 9.39(s, 1H), 4.61 (t, J = 13.3 Hz, 2H), 4.10 (t, J = 5.2 Hz, 2H), 3.85 (t, J= 12.8 Hz, 2H), 3.54 (t, J = 5.3 Hz, 2H). 64

RT 3.45 min, MI 347, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 12.65(s, 1H), 9.21 (s, 1H), 4.42 (d, J = 7.3 Hz, 1H), 4.01-3.78 (m, 2H), 3.64(d, J = 2.4 Hz, 2H), 3.55 (td, J = 11.4, 2.6 Hz, 1H), 3.50-3.36 (m, 1H),1.32 (d, J = 6.8 Hz, 3H).

General Scheme 5.

In one approach (General Scheme 5), compounds of general formula [F5-3]were prepared by a metal catalysed C—H activation coupling reaction of6-chloro-5-halo-2-iodo-pyrimidine derivatives of general formula [F5-1]with a suitable heterocycle of general formula [F5-2] utilising asuitable catalyst such as palladium acetate and a base such as cesiumcarbonate, with or without a suitable ligand such astri-tert-butylphosphonium tetrafluoroborate, in a polar solvent such astert-butanol, iso-amylalcohol or DMA at high temperature either byheating thermally or using a microwave reactor. After reaction work up,typically by a liquid-liquid extraction, the reaction product was usedcrude in the next step or purified by flash column chromatography,reverse phase preparative HPLC or re-crystallisation.6-Allyloxy-5-halo-2-heterocyclyl-pyrimidine derivatives of generalformula [F5-4] were prepared by a nucleophilic aromatic substitutiontype reaction of compounds of general formula [F5-3] utilising allylalcohol, and a suitable base such as sodium hydride in a polar solventsuch as THF at low temperature or room temperature. After reaction workup, typically by a liquid-liquid extraction, the crude product waspurified by flash column chromatography, reverse phase preparative HPLCor re-crystallisation. 5-Halo-(2-heterocyclyl)-3H-pyrimidin-4-onederivatives of general formula [F5-5] were prepared by a metal catalyseddeprotection reaction of compounds of general formula [F5-4] utilising asuitable catalyst such as[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and asuitable base such as morpholine, in a suitable solvent such asdichloromethane at ambient temperature. After reaction work up,typically by a liquid-liquid extraction, the crude product could bepurified by flash column chromatography, reverse phase preparative HPLCor re-crystallisation. In cases where the heterocycle (het) orsubstituent R′ or R″ contained an amine protected by a standard amineprotecting group such as tert-butyloxycarbonyl (Boc), compounds offormula [F5-5] are prepared by a suitable deprotection reaction, forexample reaction with an acid such as TFA or HCl in a suitable solventsuch as DCM at ambient temperature. After reaction work up, typically bya liquid-liquid extraction or purification by acidic ion exchangecatch-release, the crude product was purified by flash columnchromatography, reverse phase preparative HPLC or re-crystallisation.

Synthesis of tert-butyl(3R)-4-[5,6-dichloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(5-001)

To a thoroughly degassed stirred solution of tert-butyl(3R)-4-(5,6-dichloro-2-iodo-pyrimidin-4-yl)-3-methyl-piperazine-1-carboxylate(3-012, prepared in Scheme 3) (19.0 g, 40.2 mmol), 4-chlorothiazole (4.8g, 40.2 mmol) and cesium carbonate (19.6 g, 60.2 mmol) in tert-butanol(200 mL) was added tri-tert-butylphosphonium tetrafluoroborate (1.16 g,4.01 mmol) and palladium acetate (0.45 g, 2.014 mmol). The reaction washeated to 80° C. for 72 h. The reaction mixture was cooled to roomtemperature, filtered and the filtrate concentrated to dryness to afforda brown oil. This was purified by flash column chromatography on silicagel (eluting with a mixture of ethyl acetate in cyclohexane 0-60%) togive the title compound (3.80 g, 20%) as a yellow powder. LCMS: RT 3.34min, MI 466, Method (4LCMS6); ¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H),4.70 (s, 1H), 4.32-3.84 (m, 4H), 3.41 (td, J=13.9, 13.0, 3.3 Hz, 1H),3.17 (s, 1H), 1.49 (s, 9H), 1.37 (d, J=6.7 Hz, 3H).

Synthesis of tert-butyl(3R)-4-[6-allyloxy-5-chloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(5-002)

To a stirred solution of allyl alcohol (2.78 mL, 40.9 mmol) in THF (10mL) at 0° C. under nitrogen was added sodium hydride (60% in mineraloil, 1.63 g, 40.9 mmol) in portions. The mixture was stirred for 10 min.The allyl alcohol mixture was added drop wise to a solution oftert-butyl(3R)-4-[5,6-dichloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(5-001) (3.8 g, 8.17 mmol) in THF (20 mL) at 0° C. under nitrogen. Oncethe addition was complete the reaction was stirred for a further 10 min.Water (100 mL) was added and the mixture was extracted with ethylacetate (3×150 mL). The combined organics were dried (MgSO₄) andconcentrated to dryness to afford a yellow film. The film was purifiedusing flash chromatography on silica gel eluting with a mixture of ethylacetate in cyclohexane (0-30%). The desired fractions were concentratedto dryness to give the title compound (3.5 g, 88%) as a yellow film. ¹HNMR (400 MHz, CDCl₃) δ 8.71 (s, 1H), 6.11 (ddt, J=17.3, 10.5, 5.6 Hz,1H), 5.47 (dq, J=17.2, 1.5 Hz, 1H), 5.33-5.27 (m, 1H), 5.00 (dt, J=5.6,1.4 Hz, 2H), 4.58 (s, 1H), 4.21-3.79 (m, 3H), 3.37 (td, J=13.6, 3.3 Hz,1H), 3.23-2.9 (m, 2H), 1.49 (s, 9H), 1.32 (d, J=6.7 Hz, 3H).

Synthesis of tert-butyl(3R)-4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(5-003)

To a degassed stirred solution of tert-butyl(3R)-4-[6-allyloxy-5-chloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(5-002) (3.81 g, 7.84 mmol) and morpholine (2.06 mL, 23.5 mmol) in DCM(80 mL) under nitrogen was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.32 g, 0.392 mmol). The mixture was stirred for18 h. Water (20 mL) was added and the two phases were separated. Theaqueous was further extracted with DCM (2×20 mL) before the combinedorganics were passed through a phase separator and concentrated todryness to afford a yellow film. The film was sonicated in diethyl etherand left to sit for 90 min. A cream precipitate formed. The precipitatewas collected via vacuum filtration affording the title compound (1.74g, 49%) as a tan powder. LCMS: RT 4.49 min, MI 446, Method (4LCMS1); ¹HNMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 4.55 (s, 1H), 4.29-3.76 (m, 3H),3.36 (td, J=13.6, 3.4 Hz, 1H), 3.13 (s, 2H), 1.49 (s, 9H), 1.34 (d,J=6.7 Hz, 3H).

Synthesis of5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2R)-2-methylpiperazin-1-yl]-1H-pyrimidin-6-onehydrochloride (65)

To a stirred solution of tert-butyl(3R)-4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-3-methyl-piperazine-1-carboxylate(5-003) (1.74 g, 3.91 mmol) in DCM (20 mL) was added hydrogen chloride(19.53 mL of a 4.0 M solution in 1,4-dioxane, 78.1 mmol). The mixturewas stirred for 2 h. Ether (100 mL) was added and the resultingprecipitate was collected via vacuum filtration affording a whitepowder. The powder was dissolved in methanol (10 mL) and 2.0 M HCl indiethyl ether (10 mL) was added causing a pale yellow precipitate toform. The precipitate was collected via vacuum filtration affording ayellow powder. The yellow powder was dried in vacuo to give the titlecompound (0.843 g, 56%). LCMS: RT 1.65 min, MI 346, Method (5LCMS1); ¹HNMR (400 MHz, DMSO-d₆) δ 12.87 (s, 1H), 9.48 (s, 1H), 9.23 (s, 1H), 9.11(s, 1H), 4.64-4.49 (m, 1H), 4.11 (d, J=14.6 Hz, 1H), 3.47 (dd, J=14.8,2.9 Hz, 1H), 3.28 (d, J=12.5 Hz, 1H), 3.19 (s, 2H), 3.11 (s, 1H), 1.44(d, J=7.1 Hz, 3H).

Synthesis of tert-butyl4-[5,6-dichloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-6,6-difluoro-1,4-diazepane-1-carboxylate(5-004)

To a thoroughly degassed solution of tert-butyl4-(5,6-dichloro-2-iodo-pyrimidin-4-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate(3-003, prepared in scheme 3) (1.6 g, 3.14 mmol), 4-chlorothiazole (0.38g, 3.14 mmol) and cesium carbonate (1.54 g, 4.71 mmol) in isoamylalcohol (16 mL) was added palladium acetate (0.04 g, 0.157 mmol) andtri-tert-butylphosphonium tetrafluoroborate (0.09 g, 0.314 mmol). Themixture was heated to 90° C. for 18 h. The reaction mixture was cooledbefore being diluted with ethyl acetate and 2 M HCl, and the two phaseswere separated. The aqueous was further extracted with ethyl acetate,the combined organics were dried (MgSO₄) and concentrated to drynessaffording a dark brown film. The film was purified using flashchromatography on silica gel eluting with a mixture of ethyl acetate incyclohexanes (0-50%). The desired fractions were concentrated to drynessto give the title compound (282 mg, 18%) as a brown film. LCMS: RT 5.82min, MI 502, Method (4LCMS1); ¹H NMR (400 MHz, CDCl₃) δ 8.78 (s, 1H),4.49 (t, J=12.1 Hz, 2H), 3.94 (s, 4H), 3.86-3.77 (m, 2H), 1.49 (s, 9H).

Synthesis of tert-butyl4-[6-allyloxy-5-chloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-6,6-difluoro-1,4-diazepane-1-carboxylate(5-005)

To a stirred solution of allyl alcohol (0.18 mL, 2.62 mmol) in THF (4mL) at 0° C. under nitrogen was added sodium hydride (60% in mineraloil, 80 mg, 3.14 mmol) in portions. The mixture was stirred for 2 min.tert-Butyl4-[5,6-dichloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-6,6-difluoro-1,4-diazepane-1-carboxylate(5-004) (328 mg, 0.524 mmol) in THF (6 mL) was added to the allylalcohol solution. The mixture was stirred for 5 min. Water (20 mL) wasadded dropwise. The mixture was extracted with ethyl acetate (3×40 mL),the combined organics were dried (MgSO₄) and concentrated to dryness toafford a brown film. The residue was purified by flash chromatography onsilica gel eluting with a mixture of ethyl acetate in cyclohexane(0-30%) to afford the title compound (214 mg, 78%) as a yellow film.LCMS: RT 6.15 min, MI 522, Method (5LCMS1); ¹H NMR (400 MHz, CDCl₃) δ8.72 (s, 1H), 6.11 (ddt, J=17.2, 10.5, 5.6 Hz, 1H), 5.48 (dq, J=17.2,1.6 Hz, 1H), 5.32 (dq, J=10.4, 1.3 Hz, 1H), 5.00 (dt, J=5.6, 1.4 Hz,2H), 4.41 (t, J=12.4 Hz, 2H), 3.96-3.76 (m, 6H), 1.49 (s, 9H).

Synthesis of tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-6,6-difluoro-1,4-diazepane-1-carboxylate(5-006)

To a degassed solution of tert-butyl4-[6-allyloxy-5-chloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-6,6-difluoro-1,4-diazepane-1-carboxylate(5-005) (214 mg, 0.41 mmol) and morpholine (0.11 mL, 1.23 mmol) in DCM(6 mL) was added tetrakis(triphenyl-phosphine)palladium (20 mg, 0.021mmol). The mixture was stirred for 5 min under nitrogen. Water (10 mL)and DCM (10 mL) were added and the two phases were separated. Theorganics were concentrated to dryness affording a yellow oil. The oilwas purified using flash chromatography on silica gel, eluting with amixture of methanol in DCM (0-10% with 0.1% ammonia). The desiredfractions were concentrated to dryness to afford the title compound (135mg, 68%) as a pale yellow film. LCMS: RT 4.43 min, MI 484, Method(4LCMS1). ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H), 4.26 (t, J=12.2 Hz,2H), 3.89-3.76 (m, 6H), 1.48 (s, 9H).

Synthesis of5-chloro-2-(4-chlorothiazol-5-yl)-4-(6,6-difluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-onehydrochloride (66)

To a stirred solution of tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-6,6-difluoro-1,4-diazepane-1-carboxylate(5-006) (199 mg, 0.413 mmol) in DCM (2 mL) was added hydrogen chloride(4.63 mL of a 4 M solution in 1,4-dioxane, 18.5 mmol). The mixture wasstirred for 1 h before concentrating to dryness to afford a yellowpowder. The powder was loaded onto a SCX-2 cartridge, washed withmethanol and eluted with 2 M ammonia in methanol. The basic fractionswere concentrated to dryness to afford a yellow powder. The powder wastaken into methanol and hydrogen chloride (1 mL of a 4 M solution in1,4-dioxane) was added. The mixture was concentrated to afford the titlecompound (103 mg, 60%) as a light yellow powder. LCMS: RT 1.81 min, MI382, Method (5LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (s, 1H), 4.59 (t,J=13.2 Hz, 2H), 4.05 (s, 2H), 3.76 (t, J=13.3 Hz, 2H), 3.52-3.49 (m,2H).

The following compounds were synthesised according to the generalsynthesis shown in scheme [5]:

Number Product [F5-5] Characterisation 67

RT 1.94 min, MI 382, Method (2LCMS1); ¹H NMR (400 MHz, Methanol-d₄) δ9.08 (s, 1H), 6.51 (t, J = 54.8 Hz, 1H), 4.42 (d, J = 15.2 Hz, 1H), 3.80(d, J = 13.9 Hz, 1H), 3.76-3.64 (m, 3H), 3.59-3.56 (m, 1H), 3.52-3.44(m, 1H). 68

RT 1.84 min, MI 400, Method (5LCMS1); ¹H NMR (400 MHz, Methanol-d₄) δ9.08 (s, 1H), 5.71-5.49 (m, 1H), 4.33 (d, J = 15.1 Hz, 1H), 3.88 (d, J =14.2 Hz, 1H), 3.77 (t, J = 13.5 Hz, 1H), 3.64 (dd, J = 14.3, 5.9 Hz,1H), 3.44 (d, J = 12.8 Hz, 1H), 3.28- 3.26 (m, 1H).

General Scheme 6

In one approach (General Scheme 6), compounds of general formula [F6-3]were prepared by the reaction of an a-halo-malonate derivative ofgeneral formula [F6-1] in a condensation reaction utilising a suitablysubstituted heterocyclic carboximidamide derivative of general formula[F6-2] in a polar solvent such as methanol or THF in the presence of abase such as sodium methoxide, potassium tert-butoxide or DBU. Thereaction is suitably conducted at ambient temperature or at hightemperature either by heating thermally or using a microwave reactor.After reaction work up, typically by a liquid-liquid extraction, thereaction product was used crude in the next step or purified by flashcolumn chromatography, reverse phase preparative HPLC orre-crystallisation. Derivatives of general formula [F6-4] were preparedby the reaction of a 5-halo-2-heterocyclyl-1H-pyrimidine-4,6-dionederivative of general formula [F6-3] with a halogenating agent such asphosphorous oxychloride at high temperature. After reaction work up,typically by the addition of water followed by the addition of a basesuch as aqueous sodium hydroxide, the crude reaction mixture waspurified by liquid-liquid extraction, and the reaction product was usedcrude in the next step or purified by flash column chromatography,reverse phase preparative HPLC or re-crystallisation. Compounds ofgeneral formula [F6-6] were prepared by reaction of4,6-dichloro-5-halo-2-heterocyclyl-pyrimidine derivatives of generalformula [F6-4] in a nucleophilic aromatic substitution type reactionutilising a suitable amine of general formula [F6-5], and a base such asEt₃N or NaH, or a mineral acid such as HCl, in a polar solvent such asethanol, butanol, dioxane, DMA or DMF at high temperature either byheating thermally or using a microwave reactor. After reaction work up,typically by a liquid-liquid extraction, the reaction product was usedcrude in the next step or purified by flash column chromatography,reverse phase preparative HPLC or re-crystallisation.6-Allyloxy-5-halo-2-heterocyclyl-pyrimidine derivatives of generalformula [F6-7] were prepared by a nucleophilic aromatic substitutiontype reaction of compounds of general formula [F6-6] utilising allylalcohol, and a suitable base such as sodium hydride in a polar solventsuch as THF at low temperature or room temperature. After reaction workup, typically by a liquid-liquid extraction, the crude product waspurified by flash column chromatography, reverse phase preparative HPLCor re-crystallisation. 5-Halo-(2-heterocyclyl)-3H-pyrimidin-4-onederivatives of general formula [F6-8] were prepared by a metal catalyseddeprotection reaction of compounds of general formula [F6-7] utilising asuitable catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and a suitable base such as morpholine, in asuitable solvent such as dichloromethane at ambient temperature. Afterreaction work up, typically by a liquid-liquid extraction, the crudeproduct could be purified by flash column chromatography, reverse phasepreparative HPLC or re-crystallisation. In cases where the heterocycle(het) or substituent R′ or R″ contained an amine protected by a standardamine protecting group such as tert-butyloxycarbonyl (Boc), compounds offormula [F6-8] are prepared by a suitable deprotection reaction, forexample reaction with an acid such as TFA or HCl in a suitable solventsuch as DCM at ambient temperature. After reaction work up, typically bya liquid-liquid extraction or purification by acidic ion exchangecatch-release the crude product was purified by flash columnchromatography, reverse phase preparative HPLC or re-crystallisation.

Synthesis of 4-chlorothiazole-5-carbonitrile (6-001)

2,4-Dichloro-thiazole-5-carbonitrile (10.0 g, 55.86 mmol) was dissolvedin acetic acid (100 mL) then treated with zinc powder (10.96 g, 167.57mmol) and allowed to stir for 2 days under nitrogen at room temperature.A further 4 g of zinc was added followed by acetic acid (10 mL) and thiswas left to stir overnight. A further 2 g of zinc, followed by aceticacid (10 mL) was added and the mixture allowed to stir at roomtemperature for 48 h. The mixture was then filtered through celite,washing with methanol (300 mL) and the filtrate concentrated underreduced pressure. Ethyl acetate was added (150 mL) and the residuetriturated to form an off-white solid. This was removed by filtrationand washed with further EtOAc (100 mL). The filtrate was concentratedunder reduced pressure to afford a brown oil which was purified by flashchromatography on silica gel, eluting with 0-20% EtOAc/cyclohexane toafford the title compound (5.57 g, 69%) as a white solid. LCMS: RT 3.18min, MI 145, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H).

Synthesis of 4-chloro-N-hydroxy-thiazole-5-carboxamidine (6-002)

A solution of 4-chlorothiazole-5-carbonitrile (6-001) (5.60 g, 38.73mmol) in ethanol (129 mL) was prepared and hydroxylamine 50% w/w inwater (4.74 mL, 77.47 mmol) was added. The reaction was heated to 80° C.for 2 hours. The reaction mixture was concentrated by rotary evaporationto give the title compound (6.50 g, 94%) as a yellow solid which usedwithout further purification. LCMS: RT 1.43 min, MI 178, Method(4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 10.08 (s, 1H), 9.07 (s, 1H), 5.97(s, 2H).

Synthesis of 4-chlorothiazole-5-carboxamidine hydrochloride (6-003)

A solution of 4-chloro-N-hydroxy-thiazole-5-carboxamidine (6-002) (3.16g, 17.76 mmol) in acetic acid (59 mL) was prepared. Acetic anhydride(2.52 mL, 26.64 mmol) was added and the reaction mixture stirred at roomtemperature for 1 hour. The mixture was evacuated and back-filled withnitrogen 3 times before the addition of 10% Pd/C (0.95 g, 8.882 mmol.The mixture was then purged with hydrogen (×3) and allowed to stir undera balloon of hydrogen at room temperature overnight. Further 10% Pd/C(0.95 g, 8.882 mmol) was added and the mixture allowed to stir underhydrogen at room temperature overnight. Further 10% Pd/C (0.95 g, 8.882mmol) was added and the mixture allowed to stir under hydrogen at roomtemperature overnight. The reaction mixture was filtered through celite,washing with methanol (500 mL) and the filtrate concentrated. Theresidue was dissolved in 1,4-dioxane (10 mL) before the dropwiseaddition of 4 M hydrogen chloride solution in 1,4-dioxane (17.8 mL, 71.1mmol). The mixture was allowed to stir at room temperature for 5 minbefore the addition of diethyl ether (30 mL). The resulting tan solidwas collected by filtration, washed with further diethyl ether (20 mL)and air dried to afford the title compound (1.80 g, 43%). ¹H NMR (400MHz, DMSO-d₆) δ 9.86-9.69 (d, J=6.4 Hz, 4H), 9.44 (s, 1H).

Synthesis of 5-chloro-2-(4-chlorothiazol-5-yl)-1H-pyrimidine-4,6-dione(6-004)

To a stirred solution of 4-chlorothiazole-5-carboxamidine hydrochloride(6-003) (1.77 g, 7.53 mmol) and dimethyl chloromalonate (1.84 mL, 7.53mmol) in methanol (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene(2.36 mL, 15.8 mmol) dropwise. The mixture was stirred for 10 min atroom temperature before being heated to reflux for 2 h. The reaction wascooled to room temperature and concentrated to afford a dark red oil.The oil was purified by flash chromatography on C18 silica, eluting witha mixture of acetonitrile in water (5-50% with 0.1% formic acid). Thedesired fractions were concentrated to remove the acetonitrile beforebeing acidified to pH 2 causing brown crystals to form. The crystalswere collected via vacuum filtration to afford the title compound (0.550g, 28%) as a brown solid. LCMS: 2.37 min, MI 264; method (4LCMS1); ¹HNMR (400 MHz, Methanol-d₄) 9.12 (s, 1H).

Synthesis of 4-chloro-5-(4,5,6-trichloropyrimidin-2-yl)thiazole (6-005)

To a stirred solution of5-chloro-2-(4-chlorothiazol-5-yl)-1H-pyrimidine-4,6-dione (6-004) (550mg, 2.08 mmol) and N,N-diisopropylethylamine (1.45 mL, 8.33 mmol) intoluene (10 mL) under nitrogen was added phosphorus oxychloride (0.78mL, 8.33 mmol) dropwise and the mixture was heated at 100° C. for 1 h.The reaction was cooled to room temperature and then added dropwise to asolution of ammonium hydroxide 50:50 in ice with DCM (100 mL). Aftercomplete addition the two phases were separated and the aqueous wasfurther extracted with DCM (2×100 mL). The combined organics were washedwith a saturated aqueous sodium citrate solution (2×100 mL) before beingpassed through a phase separator. The organics were concentrated toafford a brown powder. The powder was triturated in methanol and theresulting solid was collected via vacuum filtration. The collected creamprecipitate was dried under vacuum to afford the title compound (502 mg,80%). LCMS: RT 5.29 min, MI 302, Method (4LCMS1); ¹H NMR (400 MHz,CDCl₃) δ 8.84 (s, 1H).

Synthesis of tert-butyl4-[5,6-dichloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate(6-006)

To a stirred solution of tert-butyl3-(difluoromethyl)piperazine-1-carboxylate (0.43 g, 1.83 mmol) in THF (5mL) at 0° C. under nitrogen was added sodium hydride (60% in mineraloil, 0.09 g, 2.168 mmol) in portions. Once addition was complete themixture was stirred for 20 min. The deprotonated amine solution wasadded dropwise to a stirred solution of4-chloro-5-(4,5,6-trichloropyrimidin-2-yl)thiazole (6-005) (0.50 g, 1.67mmol) in THF (5 mL) also at 0° C. under nitrogen. The mixture wasallowed to warm to room temperature with stirring for 1 h, before beingheated to reflux for 96 h. The reaction was cooled to room temperatureand diluted with ethyl acetate (200 mL). The organics were washed withwater (2×200 mL). The combined aqueous were extracted with ethyl acetate(3×200 mL). The combined organics were dried (MgSO₄) and concentrated todryness affording a brown oil. The oil was purified by flashchromatography on silica gel eluting with a mixture of ethyl acetate incyclohexane (0-100%) to afford the title compound (0.40 g, 47%) as acream powder. LCMS: 5.81 min, MI 502, Method (4LCMS1); ¹H NMR (400 MHz,DMSO-d₆) δ 9.27 (s, 1H), 6.45 (t, J=54.9 Hz, 1H), 4.94 (s, 1H), 4.26 (d,J=14.3 Hz, 1H), 4.16 (d, J=13.7 Hz, 1H), 4.08-3.95 (m, 1H), 3.60-3.47(m, 1H), 3.34-3.24 (m, 1H), 3.01 (s, 1H), 1.42 (s, 9H).

Synthesis of tert-butyl4-[6-allyloxy-5-chloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate(6-007)

To a stirred solution of allyl alcohol (0.27 mL, 4.00 mmol) in THF (10mL) at 0° C. under nitrogen was added sodium hydride (60% in mineraloil, 0.16 g, 4.00 mmol) in portions. The mixture was stirred for 10 min.The allyl alcohol mixture was added dropwise to a solution of tert-butyl4-[5,6-dichloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate(6-006) (0.4 g, 0.801 mmol) in THF (20 mL) also at 0° C. under nitrogen.Once addition was complete the reaction was stirred for a further 10min. Water (20 mL) was added dropwise and the mixture was extracted withethyl acetate (3×40 mL). The combined organics were dried (MgSO₄) andconcentrated to dryness to afford a yellow film. The film was purifiedusing flash chromatography on silica gel eluting with a mixture of ethylacetate in cyclohexane (0-30%). The desired fractions were concentratedto dryness to afford the title compound (0.358 g, 86%) as a yellow film.LCMS: 6.10 min, MI 466, Method (4LCMS1); ¹H NMR (400 MHz, CDCl₃) δ 8.72(s, 1H), 6.36-5.95 (m, 2H), 5.48 (dq, J=17.2, 1.5 Hz, 1H), 5.32 (dq,J=10.5, 1.4 Hz, 1H), 5.01 (d, J=5.5 Hz, 2H), 4.73 (s, 1H), 4.40 (d,J=14.1 Hz, 1H), 4.26-4.05 (m, 2H), 3.51 (td, J=14.1, 3.5 Hz, 1H), 3.32(dt, J=14.2, 3.7 Hz, 1H), 3.20-2.94 (m, 1H), 1.49 (s, 9H).

Synthesis of tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate(6-008)

To a degassed solution of tert-butyl4-[6-allyloxy-5-chloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate(6-007) (0.358 g, 0.685 mmol) and morpholine (0.18 mL, 2.06 mmol) in DCM(8 mL) was added tetrakis(triphenylphosphine) palladium (0.04 g, 0.034mmol). The mixture was stirred for 5 min under nitrogen. Water (10 mL)and DCM (10 mL) were added and the two phases were separated. Theorganics were concentrated to dryness to afford a yellow oil. The oilwas purified using flash chromatography on silica gel eluting with amixture of methanol in DCM (0-10% with 0.1% ammonia). The desiredfractions were concentrated to dryness to afford the title compound(0.178 g, 54%) as a pale yellow film. LCMS: 4.44 min, MI 482, Method(4LCMS1); ¹H NMR (400 MHz, CDCl₃) b 8.87 (s, 1H), 6.06 (td, J=55.9, 5.0Hz, 1H), 4.78-4.47 (m, 1H), 4.39 (d, J=14.1 Hz, 1H), 4.21 (s, 1H), 4.03(d, J=13.7 Hz, 1H), 3.48 (dd, J=12.3, 3.2 Hz, 1H), 3.25 (d, J=14.2 Hz,1H), 3.02 (s, 1H), 1.49 (s, 9H).

Chiral Separation of tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate

tert-Butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate(6-008) (0.18 g, 0.369 mmol) was dissolved to 30 mg/mL in methanol andwas then purified by SFC (Column=Lux C1 (21.2 mm×250 mm, 5 μm; Columntemperature 40° C.; Flow rate=50 mL/min, BPR=125 BarG, Isocraticconditions 40:60 MeOH:CO₂). Appropriate fractions containing the firsteluting isomer (enantiomer 1, unknown absolute stereochemistry) wereconcentrated to dryness affording tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate,enantiomer 1 (6-009) (0.0686 g, 39%) as a cream powder with 98.4% ee(RT: 2.76 min; Column details: Lux C1 4.6 mm×250 mm, 5 μm; ColumnTemperature: 40° C.; Flow Rate: 4 mL/min; Isocratic Conditions: 40:60MeOH:CO₂). LCMS: 2.49 min, MI 480, Method (4LCMS3); ¹H NMR (400 MHz,CDCl₃) δ 8.89 (s, 1H), 6.07 (td, J=55.8, 4.9 Hz, 1H), 4.63 (s, 1H), 4.39(d, J=14.1 Hz, 1H), 4.28-4.13 (m, 1H), 4.05 (d, J=13.4 Hz, 1H), 3.49(td, J=13.1, 3.4 Hz, 1H), 3.25 (d, J=13.7 Hz, 1H), 3.02 (s, 1H), 1.49(s, 9H).

The appropriate fractions containing the second eluting isomer(enantiomer 2, unknown absolute stereochemistry) were concentrated todryness affording tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate,enantiomer 2 (6-010) (0.0709 g, 40%) as a cream powder with 98.6% ee(RT: 3.16 min; Column details: Lux C1 4.6 mm×250 mm, 5 μm; ColumnTemperature: 40° C.; Flow Rate: 4 mL/min; Isocratic Conditions: 40:60MeOH:CO₂). LCMS: 2.49 min, MI 480, Method (4LCMS3); ¹H NMR (400 MHz,CDCl₃) δ 8.87 (s, 1H), 6.07 (td, J=55.9, 4.9 Hz, 1H), 4.63 (s, 1H), 4.39(d, J=14.1 Hz, 1H), 4.26-4.11 (m, 1H), 4.04 (d, J=13.7 Hz, 1H),3.56-3.43 (m, 1H), 3.25 (d, J=13.8 Hz, 1H), 3.02 (s, 1H), 1.49 (s, 9H).

Synthesis of5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-onehydrochloride, Enantiomer 1 (69)

To a stirred solution of tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate,enantiomer 1 (6-009) (69 mg, 0.142 mmol) in DCM (2 mL) was addedhydrogen chloride (1.42 mL of a 4 M solution in 1,4-dioxane, 2.85 mmol).The mixture was stirred for 20 min. Diethyl ether (10 mL) was added andthe resulting precipitate was collected via vacuum filtration. The creampowder was dried in vacuo to afford the title compound (46.1 mg, 77%).LCMS: 1.75 min, MI 382, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ13.11 (s, 1H), 9.36 (s, 1H), 9.25 (s, 1H), 8.99 (s, 1H), 6.68 (td,J=55.1, 4.8 Hz, 1H), 4.92 (t, J=13.3 Hz, 1H), 4.19 (d, J=14.5 Hz, 1H),3.63-3.51 (m, 2H), 3.42-3.24 (m, 2H), 3.19-3.04 (m, 1H).

Synthesis of5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-onehydrochloride, Enantiomer 2 (70)

To a stirred solution of tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-3-(difluoromethyl)piperazine-1-carboxylate,enantiomer 2 (6-010) (70 mg, 0.147 mmol) with DCM (2 mL) was addedhydrogen chloride (1.47 mL of a 4 M solution in 1,4-dioxane, 2.94 mmol).The mixture was stirred for 1 h. Diethyl ether (10 mL) was added and theresulting precipitate was collected via vacuum filtration. The creampowder was dried in vacuo overnight to afford the title compound (50 mg,82%). LCMS: 1.75 min, MI 382, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆)δ 13.11 (s, 1H), 9.47 (s, 1H), 9.25 (s, 1H), 9.07 (s, 1H), 6.71 (td,J=55.1, 5.0 Hz, 1H), 4.94 (s, 1H), 4.20 (d, J=14.8 Hz, 1H), 3.67-3.48(m, 2H), 3.40-3.26 (m, 2H), 3.13 (t, J=12.2 Hz, 1H).

Synthesis of tert-butyl4-[5,6-dichloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate(6-011)

A solution of 4-chloro-5-(4,5,6-trichloropyrimidin-2-yl)thiazole (6-005)(398 mg, 1.32 mmol) and triethylamine (0.19 mL, 1.39 mmol) in chloroform(11 mL) was prepared, to which tert-butyl6-fluoro-1,4-diazepane-1-carboxylate (0.29 g, 1.32 mmol) was added. Thereaction mixture was stirred for 5 days. The crude reaction mixture waspartitioned between DCM (400 mL) and water (400 mL). The organic phasewas separated and the aqueous phase was extracted further with DCM(2×200 mL). The combined organic phase was dried over MgSO₄, filteredand concentrated by rotary evaporation to give the title compound (614mg, 64%). LCMS: RT 5.72 min, MI 383, Method (4LCMS1).

Synthesis of tert-butyl4-[6-allyloxy-5-chloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate(6-012)

To a stirred solution of allyl alcohol (0.28 mL, 4.14 mmol) in THF (10mL) at 0° C. under nitrogen was added sodium hydride (60% in mineraloil, 0.17 g, 4.14 mmol) in portions. The mixture was stirred for 10 min.The allyl alcohol mixture was added dropwise to a solution of tert-butyl4-[5,6-dichloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate(6-011) (0.4 g, 0.829 mmol) in THF (20 mL) also at 0° C. under nitrogen.Once addition was completed, the reaction was stirred for a further 10min. Water (20 mL) was added dropwise and the mixture was extracted withethyl acetate (3×40 mL). The combined organics were dried (MgSO₄) andconcentrated to dryness to afford a yellow film. The film was purifiedusing flash chromatography on silica gel eluting with a mixture of ethylacetate in cyclohexane (0-30%). The desired fractions were concentratedto dryness to afford the title compound (0.290 g, 69%) as a yellow film.LCMS: 6.06 min, MI 504, Method (4LCMS1); ¹H NMR (400 MHz, CDCl₃) δ 8.71(s, 1H), 6.11 (ddt, J=17.2, 10.5, 5.6 Hz, 1H), 5.47 (dq, J=17.2, 1.6 Hz,1H), 5.31 (dq, J=10.4, 1.3 Hz, 1H), 5.22-5.01 (m, 1H), 4.99 (d, J=5.6Hz, 2H), 4.32-3.91 (m, 4H), 3.87-3.55 (m, 4H), 1.42 (s, 9H).

Synthesis of tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate(6-013)

To a degassed solution of tert-butyl4-[6-allyloxy-5-chloro-2-(4-chlorothiazol-5-yl)pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate(6-012) (290 mg, 0.575 mmol) and morpholine (0.15 mL, 1.73 mmol) in DCM(5 mL) was added Pd(dppf)C₂ complex with DCM (0.02 g, 0.029 mmol). Themixture was stirred for 5 min under nitrogen. Water (10 mL) and DCM (10mL) were added and the two phases separated. The organics wereconcentrated to dryness to afford a yellow oil. The oil was purifiedusing flash chromatography on C18 silica gel eluting with a mixture ofacetonitrile in water (5-60% with 0.1% formic acid). The desiredfractions were concentrated to dryness to afford the title compound(0.149 g, 56%) as a pale yellow powder. LCMS: 4.21 min, MI 464, Method(4LCMS1); ¹H NMR (400 MHz, CDCl₃) δ 8.88 (s, 1H), 5.42-4.78 (m, 1H),4.25-3.93 (m, 3H), 3.89-3.28 (m, 5H), 1.50-1.37 (m, 9H).

Synthesis of5-chloro-2-(4-chlorothiazol-5-yl)-4-(6-fluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-onehydrochloride (racemic) (71)

To a stirred solution of tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate(6-013) (33.0 mg, 0.071 mmol) in DCM (1.5 mL) was added hydrogenchloride (0.36 mL, 1.421 mmol, 4 M in dioxane). The mixture was allowedto stir for 3 days before concentrating under reduced pressure to affordan orange powder. The powder was sonicated into DCM (2 mL) and ether (2mL). The resulting solid was collected via vacuum filtration. Thecollected brown solid was sonicated in methanol, filtered, and thefiltrate concentrated to afford a brown powder. This was sonicated inDCM and 2 M HCl in diethyl ether. The resulting solid was collected viavacuum filtration and dried in vacuo to afford the title compound (9.7mg, 34%) as a brown powder. LCMS: RT 1.76 min, MI 364, Method (4LCMS1);¹H NMR (400 MHz, DMSO-d₆) δ 12.74 (s, 1H), 9.84 (s, 1H), 9.23 (s, 1H),9.16 (s, 1H), 5.34 (d, J=44.4 Hz, 1H), 4.44-4.29 (m, 1H), 4.27-4.12 (m,2H), 3.98-3.86 (m, 1H), 3.62-3.42 (m, 3H), 3.31 (s, 1H).

Chiral Separation of tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate

tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate(6-013) (0.15 g, 0.32 mmol) was dissolved to 30 mg/mL in methanol andwas then purified by SFC (Column=Amy-C (20 mm×250 mm, 5 μm; Columntemperature 40° C.; Flow rate=50 mL/min, BPR=125 BarG, Isocraticconditions 35:65 MeOH:CO₂). Appropriate fractions containing the firsteluting isomer (enantiomer 1, unknown absolute stereochemistry) wereconcentrated to dryness affording tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate,enantiomer 1 (6-014) (59.3 mg, 40%) as a brown powder with 100% ee (RT:2.25 min; Column details: Lux A1 4.6 mm×250 mm, 5 μm; ColumnTemperature: 40° C.; Flow Rate: 4 mL/min; Isocratic Conditions: 35:65MeOH:CO₂). LCMS: 2.41 min, MI 464, Method (4LCMS3); ¹H NMR (400 MHz,CDCl₃) δ 8.86 (s, 1H), 5.20-4.83 (m, 1H), 4.19-3.94 (m, 3H), 3.92-3.27(m, 5H), 1.49-1.40 (m, 9H).

The appropriate fractions containing the second eluting isomer(enantiomer 2, unknown absolute stereochemistry) were concentrated todryness affording tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate,enantiomer 2 (6-015) (60.4 mg, 41%) as a brown powder with 98.8% ee (RT:2.26 min; Column details: Lux A1 4.6 mm×250 mm, 5 μm; ColumnTemperature: 40° C.; Flow Rate: 4 mL/min; Isocratic Conditions: 35:65MeOH:CO₂). LCMS: 2.37 min, MI 464, Method (4LCMS3); ¹H NMR (400 MHz,CDCl₃) δ 8.87 (S, 1H), 5.18-4.88 (m, 1H), 4.18-3.95 (m, 3H), 3.93-3.27(m, 5H), 1.58-1.16 (m, 9H).

Synthesis of5-chloro-2-(4-chlorothiazol-5-yl)-4-(6-fluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-onehydrochloride, Enantiomer 1 (72)

To a stirred solution of tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate,enantiomer 1 (6-014) (0.06 g, 0.128 mmol) in DCM (2 mL) was addedhydrogen chloride (0.64 mL, 2.55 mmol) (4.0 M in 1,4-dioxane). Themixture was stirred for 20 min. The reaction mixture was thenconcentrated to dryness and suspended in ether. The resultingprecipitate was collected via vacuum filtration and dried under vacuumto afford the title compound (42.5 mg, 83%) as a brown powder. LCMS:1.71 min, MI 364, Method (4LCMS1); ¹H NMR (400 MHz, DMSO-d₆) δ 12.75 (s,1H), 9.77 (s, 1H), 9.23 (s, 1H), 9.14-8.90 (m, 1H), 5.32 (d, J=44.9 Hz,1H), 4.42-4.30 (m, 1H), 4.26-4.10 (m, 2H), 4.00-3.85 (m, 1H), 3.62-3.40(m, 4H).

Synthesis of5-chloro-2-(4-chlorothiazol-5-yl)-4-(6-fluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-onehydrochloride, Enantiomer 2 (73)

To a stirred solution of tert-butyl4-[5-chloro-2-(4-chlorothiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-6-fluoro-1,4-diazepane-1-carboxylate,enantiomer 2 (6-015) (0.06 g, 0.13 mmol) in DCM (2 mL) was addedhydrogen chloride (1.3 mL of a 4 M solution in 1,4-dioxane, 2.60 mmol).The mixture was stirred for 20 min. The reaction mixture was thenconcentrated to dryness and suspended in ether causing a brownprecipitate to form. The precipitate was collected via vacuum filtrationand dried under vacuum to afford the title compound (51.8 mg, 99%) as abrown powder. LCMS: 2.00 min, MI 364, Method (2LCMS1); ¹H NMR (400 MHz,DMSO-d₆) δ 12.75 (s, 1H), 9.78 (s, 1H), 9.23 (s, 1H), 9.07 (s, 1H), 5.34(d, J=43.9 Hz, 1H), 4.43-4.30 (m, 1H), 4.27-4.12 (m, 2H), 3.99-3.87 (m,1H), 3.65-3.39 (m, 4H).

Biology Assays and Model Systems and Methods

The compounds disclosed herein were tested for their ability to inhibitthe activity of Cdc7 according to the methods described below. Ingeneral, the compounds of Formula I were found to effectively inhibitthe activity of Cdc7.

Cdc7 Biochemical Assays Method 1

This protocol describes a method for assaying Cdc7/ASK for activity. Theassay is a 384 well ELISA assay, utilising a whole protein substrate(MCM2) and an antibody against Phospho MCM2 (S53). This site is thoughtto be specific to Cdc7/ASK phosphorylation and the assay has beenvalidated using knockout mutants.

Reagents

-   -   TBS: 25 mM Tris pH 7.2, 150 mM NaCl. (Dilute 10× stock by 1:10).    -   Wash Buffer: TBS+0.05% Tween 20. (Add 100 mL 1 M Tris pH 7.2,        120 mL 5 M NaCl and 2 mL 100% Tween 20 per 4 L).    -   Kinase Reaction Buffer: 50 mM Tris-HCl pH 8.5, 10 mM MgCl₂, 1 mM        DTT. (Dilute 10× stock by 1:10 and add 100 μL 1M DTT per 100 mL        prior to assay).    -   Diethanolamine Buffer: 1 M diethanolamine pH 9.8, 0.5 mM MgCl₂.    -   Stop Solution: 1 M NaOH.    -   MCM2 was expressed and purified in-house and used in the assay        at a final assay concentration of 436 ng/well.    -   Cdc7/ASK is purchased from commercial suppliers and used in the        assay at a final assay concentration of 37.97 ng/well or 20.63        nM.    -   ATP used as a final assay concentration of 2 μM.    -   Primary Antibody: Rabbit anti-Phospho MCM2 (S53 Antibody        (BL3353)), is purchased from commercial suppliers at 0.2 mg/mL        and used at a final assay concentration by diluting 1:800 in        TBS.    -   Secondary Antibody: Anti-Rabbit/AP Antibody is supplied is        purchased from commercial suppliers at 1 mg/mL and used at a        final assay concentration by diluting 1:2000 in TBS.    -   Development Reagent: Dissolve one 20 mg PNPP tablet (Sigma,        product N2765, 20 mg per tablet) per 20 mL diethanolamine Buffer        (or one 5 mg PNPP tablet per 5 mL diethanolamine buffer). Cover        in foil and leave shaking on a roller shaker at room temperature        for up to an hour to dissolve.

Methods

-   -   1. Add 20 μL 1× working stock of Substrate (MCM2) in TBS to all        wells of a clear, 384 well, Nickel-chelate microplate to give a        final concentration of 250 ng/well. Incubate at room temperature        for at least 1 hour. Plates can be pre-coated for 1 hour and        stored at 4° C. for up to 8 days.    -   2. Wash with TBS+0.05% Tween 20 (80 μL x 3).    -   3. Add 2 μL 10× test compounds, including the positive control,        in 40% DMSO/water to ‘test’ wells. Add 2 μL 40% DMSO/water to        ‘control’ and ‘blank’ wells. The final DMSO concentration will        be 4%.    -   4. Add 13 μL CDC7/ASK Kinase (1.5× stock) in Kinase Reaction        Buffer to ‘test’ and ‘control’ wells to give a final        concentration of 5 ng/well. Add 13 μL Kinase Reaction Buffer to        ‘blank’ wells.    -   5. Add 5 μL ATP (4× stock) in Kinase Reaction Buffer to all        wells to give a final concentration of 2 μM.    -   6. Incubate at room temperature for 90 minutes.    -   7. Wash with TBS+0.05% Tween 20 (80 μL x 3).    -   8. Add 20 μL 1× working solution of Primary Antibody in TBS to        all wells. Incubate at room temperature for 30 minutes.    -   9. Wash with TBS+0.05% Tween 20 (80 μL x 3).    -   10. Add 20 μL 1× working solution of Secondary Antibody in TBS        to all wells. Incubate at room temperature for 30 minutes.    -   11. Wash with TBS+0.05% Tween 20 (80 μL x 3).    -   12. Add 20 μL 1× Development Reagent to all wells.    -   13. Incubate at room temperature for 2 hours. Stop the reaction        by adding 20 μL Stop Solution to all wells and record Absorbance        on a Pherastar plate reader.

Percentage inhibition values were calculated from absorbance values,using the no compound (DMSO) and no enzyme control values as 0% and 100%inhibition, respectively. IC₅₀ determination was performed with ExcelFitsoftware (IDBS) using curve fit 205. Z′ factors were determined for eachplate tested and were all above 0.5.

Method 2

This protocol describes a method for assaying a compounds' ability toinhibit Cdc7 activity by measuring pS40MCM2 levels in a Cdc7/Dbf4 EnzymeTR-FRET Assay.

2.5 nM Cdc7/Dbf4 was incubated with 100 nM of biotin-labelled peptide35-TDALTS(pS)PGRDLP in the presence of 1 μM ATP at 25° C. for 120minutes. The phosphorylation of the peptide was detected using TR-FRET.Anti-Mcm2 (pS40) antibody, Terbium anti-rabbit secondary antibody andStreptavidin-Alexa Fluor488 form the detection system.

Method 3

This protocol describes a method for assaying Cdc7/ASK for activity. Theassay is an off-chip mobility shift assay (MSA) run at CarnaBiosciences.

Materials and Methods 1. Preparation of Test Compound Solution.

The test compound was dissolved in and diluted with dimethylsulfoxide(DMSO) to achieve 100-fold higher concentration which was specified bythe sponsor. Then the solution was further 25-fold diluted with assaybuffer to make the final test compound solution. Reference compounds forassay control were prepared similarly.

2. Kinase

Cdc7/ASK: Full-length human Cdc7 [1-574(end) amino acids of accessionnumber NP_003494.1] was co-expressed as N-terminal GST-fusion protein(92 kDa) with Dbf4(ASK) [1-674(end) amino acids of accession numberNP_006707.1] using baculovirus expression system. GST-Cdc7 was purifiedby using glutathione sepharose chromatography.

3. Assay Reagents and Procedures Off-Chip Mobility Shift Assay (MSA)

1) The 5 mL of x4 compound solution, 5 mL of x4 Substrate/ATP/Metalsolution, and 10 mL of ×2 kinase solution were prepared with assaybuffer (20 mM HEPES, 0.01% Triton X-100, 1 mM DTT, pH 7.5) and mixed andincubated in a well of polypropylene 384 well microplate for 5 hours atroom temperature.2) 70 mL of Termination Buffer (QuickScout Screening Assist MSA; CarnaBiosciences) was added to the well.3) The reaction mixture was applied to LabChip system (Perkin Elmer),and the product and substrate peptide peaks were separated andquantitated.4) The kinase reaction was evaluated by the product ratio calculatedfrom peak heights of product (P) and substrate (S) peptides (P/(P+S)).

4. Reaction Conditions

Substrate ATP (μM) Metal Positive Kinase Platform Name (nM) Km AssayName (mM) control Cdc7/ASK MSA MCM2 peptide 1000 2.8 5 Mg 10StaurosporineReaction time is 5 hours.

5. Data Analysis

The readout value of reaction control (complete reaction mixture) wasset as a 0% inhibition, and the readout value of background (Enzyme(−))was set as a 100% inhibition, then the percent inhibition of each testsolution was calculated.IC₅₀ value was calculated from concentration vs. % Inhibition curves byfitting to a four parameter logistic curve.

Results

Biochemical Biochemical Biochemical method 1 Method 2 method 3 Number(pIC₅₀) (pIC₅₀) (pIC₅₀) 1 6.64 2 8.50 3 7.24 4 8.79 5 6.90 6 8.42 8.71 76.61 8 7.52 9 6.25 10 7.03 11 6.16 12 6.44 13 7.48 14 8.74 15 7.43 168.56 8.14 17 8.92 8.84 18 7.22 19 7.39 20 8.35 21 8.40 22 8.36 23 8.4824 8.40 25 8.32 26 8.78 27 7.25 28 8.68 29 8.50 30 8.46 31 8.44 32 8.0633 8.57 34 6.80 35 8.85 36 8.23 37 8.48 38 8.64 39 7.67 8.13 40 8.43 419.08 8.4 42 8.42 43 8.74 8.41 44 8.57 8.21 45 8.71 46 8.78 47 9.11 488.65 49 7.29 50 7.36 51 8.23 52 8.15 53 8.89 54 7.14 56 7.35 57 8.19 588.15 59 8.13 60 7.7 61 7.89 62 7.67 63 8.26 64 8.38 65 8.41 66 8.37 678.22 68 8.16 69 8.47 70 8.17 71 8.24 72 8.42 73 7.99

Cdc7 Cell Pharmacodynamics Assays Method 1

This protocol describes a method to investigate the inhibition of Cdc7activity of compounds by measuring pS53MCM2 levels in cells aftertreatment.

Reagents

-   -   HCT116 cells (wild type P53 positive)    -   McCoys 5A media (PAA Laboratories Ltd, E15-022)    -   10% FCS (Sera Laboratories International Ltd, EU000F        Batch:108005)    -   100× L-Glutamine (Invitrogen, 25030-024)    -   D-PBS without CaCl₂ and MgCl₂ (Invitrogen, ref. 14190-094)    -   Trypsin/EDTA (Invitrogen 25300-054)    -   2% BSA in PBS    -   Cell Extraction Buffer (Invitrogen FNN0011)    -   Protease inhibitor cocktail (Sigma P-2714)    -   PMSF 0.3M stock in DMSO (Sigma P7626)    -   Antibody-rabbit pMCM2 Ser53 (Bethyl #A300-756A)    -   Antibody-goat MCM2 (Bethyl #A300-122A)    -   Antibody-goat Anti Rabbit IgG HRP (Perbio Science UK Ltd 31462)    -   1×PBS    -   FACE Wash buffer (0.02% Triton X100 in 1×PBS)    -   SuperSignal ELISA Pico Chemiluminescent Substrate (Perbio        Science UK Ltd 37070)

Method

-   -   72 hours prior to the start of the experiment plate 1×10⁶ HCT116        cells in a 150 cm² flask in complete McCoys 5A media (+10%        FCS+1× L-glutamine).    -   Plate 20,000 HCT116 cells per well in standard TC treated 96        well plate in 100 μL complete McCoys 5A media.    -   Allow cells to settle overnight in incubator set at 37° C. and        5% CO₂.    -   Remove intermediate plate from fridge and place at 37° C.        overnight to allow to equilibrate.    -   Cell treatment: cell assay plate 100 μL; daughter to cell        transfer volume 3.33 μL; daughter volume 45 μL; mother plate to        daughter volume 5 μL.    -   Once all cells are treated remove the cells to the incubator and        incubate for 6 hours.    -   Dilute the capture antibody (total MCM2 #A300-122A) 1 in 250 in        the required volume of PBS (5 mL per assay plate) and add 50 μL        to each well of a Hybond plate excluding wells 12E to 12H. In        these wells add 50 μL PBS. Seal the plate and incubate at room        temperature for a minimum of 2 hours.    -   Defrost aliquot of Invitrogen Cell Extraction Buffer (FNN0011)        on ice and supplement with appropriate volume of both Sigma        protease inhibitor cocktail (P-2714) and PMSF (final conc 1 mM        from a 1 M stock in DMSO).    -   After the 6 hour cell treatment time tap out the media from the        assay plates and place them in the −70° C. freezer for at least        5 minutes.    -   Remove plates from freezer and add 20 μL of ice cold complete        lysis buffer on ice. Incubate cells for 30 minutes at 4° C.    -   Add 80 μL per well 2% BSA.    -   Transfer 80 μL from the lysis plate to the same wells in the        capture/ELISA plate. Cover with plate seal and incubate plates        overnight at 4° C.    -   Wash plates with PBS, remove any residual remaining liquid and        add 50 μL per well of pMCM2 Ser53 antibody (#A300-756A) diluted        1 in 100 in 2% BSA. Cover plate and incubate at room temperature        for 2 hours with gentle shaking.    -   Wash plates with PBS, remove any residual remaining liquid and        Incubate with 50 μL goat anti rabbit antibody (1 in 800 dilution        in 2% BSA) for 1 hour at room temperature.    -   Wash plates with PBS, remove any residual remaining liquid and        add 50 μL mixed SuperSignal Pico substrate.    -   Incubate each plate for 5 minutes at room temperature shielding        the plates from direct light (with a cover plate). Read plates        with the luminescent detection.

Method 2

This protocol describes a method to investigate the inhibition of Cdc7activity by measuring pS40MCM2 levels in cells, after treatment withcompounds.

Reagents

-   -   HCT116 cells (ATCC, #CCL-247)    -   McCoys 5A with L-glutamine (Cellgro, #10-050-CV)    -   10% FCS (Cellgro, #35-010-CV)    -   D-PBS without CaCl₂ and MgCl₂ (Cellgro, #21-031-CV)    -   Trypsin/EDTA (Cellgro, #25-052-CL)    -   BSA (Calbiochem, 126593)    -   Cell Extraction Buffer (Invitrogen FNN0011)    -   Protease inhibitor cocktail (Sigma P-2714)    -   PMSF 0.3M stock in DMSO (Sigma P7626)    -   Antibody-rabbit pMCM2 Ser40 (Abcam, AB133243)    -   Antibody-goat MCM2 (Bethyl #A300-122A)    -   Antibody-goat Anti Rabbit IgG HRP (Thermo, 31462)    -   SuperSignal ELISA Pico Chemiluminescent Substrate (Perbio        Science UK Ltd 37069)    -   10×PBS (Growcells, MRGF-6236)    -   Triton X100 (Sigma, P-T8787)    -   DMSO (Fisher, D128-1)    -   2-Propanol (J.T. Baker, 9095-03)

Method

-   -   Seed 1×10⁶ HCT116 cells into each of two 175 cm² flask        containing 30 mL Cell Growth Media and incubate at 37° C., 5%        CO₂ for 3 days.    -   Harvest the cells from one T175 cm² flask and count.    -   Dilute with Cell Growth Media to a cell density of 2×10⁵.        Dispense 100 μL to each well (20,000 HCT116 cells/well) of TC        treated 96-well plate(s).    -   Allow cells to settle overnight in incubator set at 37° C. and        5% CO₂.    -   Cell treatment: Transfer 0.25 μL/well from the compound plate to        the wells of the cell plate(s). This is a 1:400 dilution of        compound in the assay.    -   Once all cells are treated place the cells back to the incubator        and incubate for 18 hours.    -   Dilute the capture antibody (total MCM2 #A300-122A) 1 in 250 in        the required volume of PBS (5 mL per assay plate, plus 5 mL for        dead volume) and add 50 μL to each well of a Hybond plate except        wells A12 & B12. Seal the plate and incubate at room temperature        for a minimum of 2 hours.    -   Defrost aliquot of Invitrogen Cell Extraction Buffer (FNN0011)        on ice and supplement with appropriate volume of both Sigma        protease inhibitor cocktail (P-2714) and PMSF (final conc 1 mM        from a 1 M stock in DMSO).    -   After the 6 hour or 18 hour cell treatment time, tap out the        media from the assay plates and place them in the −70° C.        freezer for at least 5 minutes.    -   Flick out the remaining liquid in the previously prepared        capture Ab plate(s) and add 200 μL 2% BSA per well. Incubate for        1 hour at room temperature.    -   Remove plates from freezer and add 20 μL of ice cold complete        lysis buffer. Incubate cells for 30 minutes at 4° C.    -   Add 30 μL per well 2% BSA    -   At the end of the 1 hour incubation, wash the Capture/ELISA        plate(s) with Wash Buffer on the BioTek plate washer.    -   Transfer 40 μL per well of the lysis plate(s) to the same wells        in the Capture/ELISA plate. Incubate cells overnight at 4° C.    -   At the end of the overnight incubation, wash the ELISA plate(s)        with Wash Buffer on BioTek plate washer.    -   Prepare Detection Antibody Buffer and dispense 50 μL to all        wells of ELISA plate(s) except wells G1 & H1. Cover plate and        incubate at room temperature for 2 hours with gentle shaking.    -   At the end of the 2 hour incubation, wash the ELISA plate(s)        with Wash Buffer on the BioTek plate washer.    -   Prepare the Conjugated Antibody Buffer and dispense 50 μL to all        wells of ELISA plate(s).    -   Cover the plate and incubate at room temperature for 1 hour with        gentle shaking.    -   At the end of the 1 hour incubation, wash the ELISA plate(s)        with Wash Buffer on the BioTek plate washer.    -   Prepare Substrate Buffer and dispense 50 μL to all wells of        ELISA plate(s).    -   Incubate for a minimum of 10 minutes and read plates on the        EnVision 2100 Multilabel Reader (Mirror: Luminescence (404) &        Luminescence 700 (212); Measurement Height: 6.5 mm; Measurement        Time: 0.2 s).

Method 3

This protocol describes a method to investigate the inhibition of Cdc7activity by measuring pS53MCM2 levels in cells, after treatment withcompounds.

Reagents

-   -   SW48 cells    -   RPMI 1640 (Sigma, R5886)    -   10% FCS (Sera Laboratories International Ltd, EU000F        Batch:108005)    -   100× L-Glutamine (Invitrogen, 25030-024)    -   D-Glucose Solution (10%) (Sigma, G8644)    -   HEPES Buffer Solution (Sigma, 83264)    -   Sodium Pyruvate (Sigma, S8636)    -   PBS (Fisger, BP399-4)    -   Trypsin/EDTA (Invitrogen 25300-054)    -   2% BSA in PBS    -   Cell Extraction Buffer (Invitrogen FNN0011)    -   Protease inhibitor cocktail (Sigma P-2714)    -   PMSF 0.3M stock in DMSO (Sigma P7626)    -   Antibody-rabbit pMCM2 Ser53 (Bethyl #A300-756A)    -   Antibody-goat MCM2 (Bethyl #A300-122A)    -   Antibody-goat Anti Rabbit IgG HRP (Perbio Science UK Ltd 31462)    -   SuperSignal ELISA Pico Chemiluminescent Substrate (Perbio        Science UK Ltd 37070)

Method

-   -   Plate 30,000 SW48 cells per well in standard TC treated 96 well        plate in 100 μL complete RPMI 1640 medium.    -   Allow cells to settle overnight in incubator set at 37° C. and        5% CO₂.    -   Cell treatment: prepare a 384 well plate containing 80 μl        PBS/well. The PBS should be at room temperature—to be referred        to as intermediate plate. Transfer 2 μL of compound from mother        plate to intermediate (daughter plate) 1:40 dilution, then 5 μL        intermediate to cell (daughter) plate.    -   Once all cells are treated place the cells back to the incubator        and incubate for 6 hours.    -   Dilute the capture antibody (total MCM2 #A300-122A) 1 in 250 in        the required volume of PBS (5 mL per assay plate, plus 5 mL for        dead volume) and add 50 μL to each well of a Hybond plate. Seal        the plate and incubate at room temperature for a minimum of 2        hours.    -   Defrost aliquot of Invitrogen Cell Extraction Buffer (FNN0011)        on ice and supplement with appropriate volume of both Sigma        protease inhibitor cocktail (P-2714) and PMSF (final conc 1 mM        from a 1 M stock in DMSO).    -   After the 6 hour cell treatment time, tap out the media from the        assay plates and place them in the −80° C. freezer for at least        5 minutes.    -   Remove plates from freezer and add 20 μL of ice cold complete        lysis buffer, with the multidrop. Incubate cells for 30 minutes        at 4° C.    -   Add 80 μL per well 2% BSA.    -   Flick out the remaining liquid from the capture plate and        transfer 80 μL from the lysis plate to the same wells in the        capture/ELISA plate, using the Biomek. Cover with plate seal and        incubate plates overnight at 4° C.    -   Wash plates with PBS, remove any residual remaining liquid and        add 50 μL per well of pMCM2 Ser53 antibody (#A300-756A) diluted        1 in 100 in 2% BSA. Cover plate and incubate at room temperature        for 2 hours with gentle shaking.    -   Wash plates with PBS, remove any residual remaining liquid and        Incubate with 50 μL goat anti rabbit antibody (1 in 800 dilution        in 2% BSA), for 1 hour at room temperature.    -   Wash plates with PBS, remove any residual remaining liquid and        add 50 μL mixed SuperSignal Pico substrate.    -   Incubate each plate for 5 minutes at room temperature shielding        the plates from direct light (with a cover plate). Read plates        with the luminescent detection.

Results

Biomarker Biomarker Biomarker Method 1 Method 2 Method 3 Number (pEC₅₀)(pEC₅₀) (pEC₅₀) 2 5.70 4 7.34 5.83 6 6.97 5.68 8 6.48 12 5.44 13 5.96 146.80 5.61 15 5.76 17 6.95 6.43 23 5.41 25 6.35 28 7.34 5.96 29 6.80 306.60 31 7.07 32 6.58 33 7.00 35 7.62 36 6.80 37 6.96 38 7.08 39 6.47 406.71 41 8.14 6.50 42 6.41 43 7.42 6.46 44 7.60 6.14 45 7.35 5.93 46 6.8247 7.42 5.93 48 6.34 49 5.34 50 5.44 52 6.07 5.24 53 7.48 6.02 55 7.0056 5.38 57 6.14 58 6.48 59 6.14 60 5.91 61 6.79 62 6.01 63 6.28 64 6.7865 7.42 66 7.12 67 7.01 68 6.70 69 7.78 70 6.49 71 6.60 72 7.02 73 5.88

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference in theirentirety and to the same extent as if each reference were individuallyand specifically indicated to be incorporated by reference and were setforth in its entirety herein (to the maximum extent permitted by law).

All headings and sub-headings are used herein for convenience only andshould not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise paragraphed. No language in the specification should beconstrued as indicating any non-paragraphed element as essential to thepractice of the invention.

The citation and incorporation of patent documents herein is done forconvenience only and does not reflect any view of the validity,patentability, and/or enforceability of such patent documents.

This invention includes all modifications and equivalents of the subjectmatter recited in the paragraphs appended hereto as permitted byapplicable law.

1. A compound of Formula I:

or a salt or solvate thereof wherein, X is chosen from halogen,haloC₁-C₆alkyl, NO₂, OCN, SCN, —C(═O)NR⁵R⁶, —NHS(O)₂R⁶, and CN; R² is agroup A-B-C wherein, A is a bond or is C₁-C₁₀alkyl; B is absent or ischosen from S(O)_(p), NR³, O, C₂-C₁₀alkenyl, and C₂-C₁₀alkynyl; and C isa 3 to 15 membered heterocycloalkyl group or a 4 to 11 memberedcycloalkyl group either of which is optionally substituted with one ormore R⁵ groups; R¹ is a heteroaryl group of Formula A

wherein Z¹ is selected from C and N, Z² is selected from CR^(a), NR^(b),N, O and S, Z³ is selected is N and NR^(c), Z⁴ and Z⁵ are independentlyselected from O, N, S, NR^(d) and CR^(e); R^(a) is selected fromhydrogen, hydroxyl, halogen, COOR³, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl,C₀-C₆alkylheterocycloalkyl, C₀-C₆alkylheteroaryl, C₀-C₆alkylCN,C₀-C₆alkylC(═O)C₀-C₆alkylR³, C₀-C₆alkylC(═O)C₀-C₆alkylOR³,C₀-C₆alkylC(═O)C₀-C₆alkylNR³R⁴, haloC₁-C₆alkyl, NO₂, C₀-C₆alkylNR³R⁴,C₀-C₆alkylNR³C₀-C₆alkylOR⁴, C₀-C₆alkylOS(═O) R⁴, —C₀-C₆alkylOS(═O)₂R⁴,—C₀-C₆alkylS(═O)_(p)R⁴, —OCN, and —SCN, wherein any of the foregoing isoptionally substituted with one or more R⁵ groups; and R^(b) and R^(c)are independently selected from hydrogen, C₁-C₆ alkyl and C₃-C₆cycloalkyl; or R^(a) and R^(c) are taken together to form a fused6-membered ring optionally substituted with one or more R⁵ groups; R^(d)is selected from hydrogen, C₁-C₆ alkyl and C₃-C₆ cycloalkyl; R^(e) isselected from hydrogen, hydroxyl, halogen, OR³, COOR³, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl,C₀-C₆alkylheterocycloalkyl, C₀-C₆alkylheteroaryl, C₀-C₆alkylCN,C₀-C₆alkylC(═O)C₀-C₆alkylR³, C₀-C₆alkylC(═O)C₀-C₆alkylOR³,C₀-C₆alkylC(═O)C₀-C₆alkylNR³R⁴, haloC₁-C₆alkyl, NO₂, C₀-C₆alkylNR³R⁴,C₀-C₆alkylNR³C₀-C₆alkylOR⁴, C₀-C₆alkylOS(═O) R⁴, —C₀-C₆alkylOS(═O)₂R⁴,—C₀-C₆alkylS(═O)_(p)R⁴, —OCN, and —SCN; or two adjacent R^(e) groups,adjacent R^(c) and R^(e) or adjacent R^(e) and R^(d) groups are takentogether to form a fused 6-membered ring optionally substituted with oneor more R⁵ groups; each R³ and R⁴ are each independently chosen from H,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, haloC₁-C₆alkyl, C₀-C₆alkylaryl,C₀-C₆alkylcycloalkyl, C₀-C₆alkylheteroaryl, C₀-C₆alkylheterocycloalkyl,wherein any of the foregoing, except for H, is optionally substitutedwith one or more R⁵; or R³ and R⁴ are taken together to form a 3 to 7membered carbocyclic or heterocyclic ring system, wherein said ringsystem is optionally substituted with one or more R⁵; each R⁵ isindependently chosen from halogen, hydroxyl, OR⁶, C₁-C₁₀alkyl,C₂-C₁₀alkenyl, C₂-C₁₀alkynyl, C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl,C₀-C₆alkylheterocycloalkyl, C₀-C₆alkylheteroaryl, —C₀-C₆alkylCN,—C₀-C₆alkylC(═O)C₀-C₆alkylR⁶, —C₀-C₆alkylC(═O)C₀-C₆alkylOR⁶,—C₀-C₆alkylC(═O)C₀-C₆alkylNR⁶R⁶, —C₀-C₆alkylC(═O)C₀-C₆alkylNR⁶C(═O)OR⁶,haloC₁-C₆alkyl, NO₂, —C₀-C₆alkylNR⁶R⁶, —C₀-C₆alkylNR⁶C₀-C₆alkylOR⁶,—C₀-C₆alkylNR⁶C₀-C₆alkylC(═O)R⁶, —C₀-C₆alkylOR⁶, (═O),—C₀-C₆alkylOC(═O)C₀-C₆alkylR⁶, —C₀-C₆alkylOC(═O)C₀-C₆alkylNR⁶R⁶,—C₀-C₆alkylOC(═O)C₀-C₆alkylOR⁶, —C₀-C₆alkylOS(═O) R⁶,—C₀-C₆alkylOS(═O)₂R⁶, —C₀-C₆alkylOS(═O)₂C₀-C₆alkylOR⁶,—C₀-C₆alkylOS(═O)₂C₀-C₆alkylNR⁶R⁶, —C₀-C₆alkylS(═O)_(p)R⁶,—C₀-C₆alkylS(═O)₂C₀-C₆alkylNR⁶R⁶, —C₀-C₆alkylS(═O)C₀-C₆alkylNR⁶R⁶,wherein each of the foregoing is optionally substituted with R⁷, ortogether with carbon atoms to which they are attached, two R⁵ groups arelinked to form a fused aryl, heteroaryl, 3 to 6 memberedheterocycloalkyl or a 3 to 6 membered cycloalkyl; each R⁶ isindependently chosen from H, C₁-C₁₀alkyl, C₂-C₁₀alkenyl, C₂-C₁₀alkynyl,haloC₁-C₆alkyl, C₀-C₆alkylaryl, C₀-C₆alkylcycloalkyl,C₀-C₆alkylheteroaryl, C₀-C₆alkylheterocycloalkyl, wherein each of theforegoing is optionally substituted with R⁷; or two R⁶ are takentogether to form a 3 to 15 membered carbocyclic or heterocyclic ringsystem, wherein said ring system is optionally substituted with one ormore R⁷; each R⁷ is independently chosen from halogen, hydroxyl,C₁-C₆alkyl, OC₁-C₆alkyl, and haloC₁-C₆alkyl; and each p is independently0, 1 or 2; with the proviso that the compound of Formula I is not one ofthe following compounds:6-cyclopentyl-5-iodo-2-(5-thiazolyl)-4(3H)-pyrimidinone;6-cyclopentyl-2-(1-ethyl-1H-pyrazol-4-yl)-5-iodo-4(3H)-pyrimidinone;6-cyclopentyl-5-iodo-2-(1-propyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1-ethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1-propyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1-isopropyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;6-cyclopentyl-5-iodo-2(1-isopropyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(5-thiazolyl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(3,5-dimethyl-4-isoxazolyl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1-propyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;6-cyclopentyl-5-iodo-2-(1 methyl-1H-pyrazol-3-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1-cyclopropyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1-methyl-1H-pyrazol-3-yl)-4(3H)-Pyrimidinone;5-bromo-6-cyclopentyl-2(1,5-dimethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;6-cyclopentyl-5-iodo-2(1,3,5-trimethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;6-cyclopentyl-5-iodo-2-[1(1-methylethyl)-1H-imidazol-5-yl]-4(3H)-pyrimidinone;6-cyclopentyl-5-iodo-2-(1-propyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;6-cyclopentyl-2-(1-ethyl1H-imidazol-5-yl)-5-iodo-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1-methyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1-methyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;6-cyclopentyl-5-iodo-2-(1 methyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1,3-dimethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;6-cyclopentyl-2-(1,3-dimethyl-1H-pyrazol-4-yl)-5-iodo-4(3H)-pyrimidinone;6-cyclopentyl-2-(3,5-dimethyl-4-isoxazolyl)-5-iodo-4(3H)-pyrimidinone;6-cyclopentyl-5-iodo-2-(1-methyl-1H-imidazol-5-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2-[1(1-methylethyl)-1H-imidazol-5-yl]-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(3-ethyl-1-methyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1,3,5-trimethyl-1H-pyrazol-4-yl)-4(3H)-pyrimidinone;6-cyclopentyl-2-(1,5-dimethyl-1H-pyrazol-4-yl)-5-iodo-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1-ethyl-1H-imidazol-5-yl)-4(3H)-Pyrimidinone;6-cyclopentyl-2-(1-cyclopropyl-1H-imidazol-5-yl)-5-iodo-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1H-1,2,4-triazol-5-yl)-4(3H)-pyrimidinone;6-cyclopentyl-2-(3-ethyl-1-methyl-1H-pyrazol-4-yl)-5-iodo-4(3H)-pyrimidinone;6-cyclopentyl-5-iodo-2-(1H-1,2,3-triazol-5-yl)-4(3H)-pyrimidinone;6-cyclopentyl-5-iodo-2-(1H-1,2,4-triazol-5-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1H-1,2,3-triazol-5-yl)-4(3H)-pyrimidinone;6-cyclopentyl-5-iodo-2-(1-propyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1-propyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1-methyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;6-cyclopentyl-5-iodo-2-(1-methyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone;5-bromo-6-cyclopentyl-2(1-ethyl-1H-pyrazol-5-yl)-4(3H)-pyrimidinone; and6-cyclopentyl-2-(1-ethyl-1H-pyrazol-5-yl)-5-iodo-4(3H)-pyrimidinone. 2.A compound according to claim 1 wherein X is chosen from fluoro, chloro,bromo, iodo and CN.
 3. A compound according to any one of the precedingclaims wherein X is chloro.
 4. A compound according to any one of thepreceding claims, wherein R² is a group A-B-C wherein: A is a bond; B isabsent; and C is a 3 to 7 membered heterocycloalkyl or a 4 to 8 memberedcycloalkyl either of which is optionally substituted with one or more R⁵group.
 5. A compound according to any one of the preceding claimswherein C is selected from a 5 to 7 membered heterocycloalkyl which isoptionally substituted with one of more R⁵ group.
 6. A compoundaccording to any one of the preceding claims wherein C is selected from:

each optionally substituted with one of more R⁵ group.
 7. A compoundaccording to any one of the preceding claims wherein C is selected from

each optionally substituted with one of more R⁵ group.
 8. A compoundaccording to any one of the preceding claims wherein R⁵ is selected fromhalogen, hydroxyl, OR⁶, C₁-C₁₀alkyl, —C₀-C₆alkylC(═O)C₀-C₆alkylR⁶,—C₀-C₆alkylC(═O)C₀-C₆alkylOR⁶, haloC₁-C₆alkyl, —C₀-C₆alkylOR⁶ and (═O),wherein each of the foregoing is optionally substituted with R⁷.
 9. Acompound according to any one of the preceding claims wherein R⁵ isselected from halogen, hydroxyl, C₁-C₃alkyl, haloC₁-C₆alkyl and (═O).10. A compound according to any one of the preceding claims wherein R⁵is selected from fluoro, chloro, methyl, trifluoromethyl anddifluoromethyl.
 11. A compound according to any one of the precedingclaims wherein Z¹ is C.
 12. A compound according to any one of thepreceding claim wherein Z² is CR^(a).
 13. A compound according to anyone of the preceding claims wherein Z³ is N.
 14. A compound according toany one of the preceding claims wherein R¹ is a heteroaryl group ofFormula A1:

wherein R^(a), Z⁴ and Z⁵ are as defined in claim
 1. 15. A compoundaccording to any one of the preceding claims wherein R¹ is a heteroarylgroup of formula A2:

wherein R^(a), R^(e) and Z⁵ are as defined in claim
 1. 16. A compoundaccording to any one of the preceding claims wherein R¹ is a heteroarylgroup of formula A3:

wherein R^(a), R^(e) and Z⁴ are as defined in claim
 1. 17. A compoundaccording to any one of the preceding claims wherein R¹ is selectedfrom:


18. A compound according to any one of the preceding claims wherein R¹is selected from


19. A compound according to any one of the preceding claims whereinR^(a) is selected from hydrogen, hydroxyl, halogen, C₁-C₃alkyl, —OCN,—SCN, —CN and haloC₁-C₃alkyl.
 20. A compound according to any one of thepreceding claims wherein R^(e) is selected from hydrogen, hydroxyl,halogen, C₁-C₃alkyl, —OCN, —SCN, —CN and haloC₁-C₃alkyl.
 21. A compoundaccording to any one of the preceding claims wherein R^(a) is selectedfrom hydrogen, hydroxyl, fluoro, chloro, methyl, ethyl, trifluoromethyl,and difluoromethyl.
 22. A compound according to any one of the precedingclaims wherein R^(a) is selected from hydrogen, hydroxyl, fluoro,chloro, methyl, ethyl, trifluoromethyl, and difluoromethyl.
 23. Acompound according to any one of the preceding claims wherein R^(b) isselected from hydrogen and methyl.
 24. A compound according to any oneof the preceding claims wherein R¹ is selected from:


25. A compound selected from: tert-butyl4-[5-chloro-2-(4-methylthiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]piperidine-1-carboxylate;5-chloro-2-(4-methylthiazol-5-yl)-4-(4-piperidyl)-1H-pyrimidin-6-one;5-chloro-4-[1-(2,2-difluorocyclopropanecarbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-[1-(4-methylthiazole-5-carbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-2-(4-methylthiazol-5-yl)-4-[1-(thiazole-4-carbonyl)-4-piperidyl]-1H-pyrimidin-6-one;5-chloro-4-[1-(3-methyl-1H-pyrazole-5-carbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-[1-(1,5-dimethylpyrazole-3-carbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-[1-(2,5-dimethylpyrazole-3-carbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-[1-(5-methylisoxazole-3-carbonyl)-4-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-2-(4-methylthiazol-5-yl)-4-[1-(pyridazine-4-carbonyl)-4-piperidyl]-1H-pyrimidin-6-one;5-chloro-4-(1-isobutyl-4-piperidyl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-2-(4-methylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;5-chloro-2-(5-ethyl-1H-pyrazol-4-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;5-chloro-4-tetrahydropyran-4-yl-2-thiazol-5-yl-1H-pyrimidin-6-one;5-chloro-2-(4-methylthiadiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;5-chloro-2-(4-methyloxazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;5-fluoro-2-(4-methylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;5-bromo-2-(4-methylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;5-iodo-2-(4-methylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;2-(4-methylthiazol-5-yl)-6-oxo-4-tetrahydropyran-4-yl-1H-pyrimidine-5-carbonitrile;5-chloro-2-(2-hydroxy-4-methyl-thiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;5-chloro-4-(4-hydroxy-1-piperidyl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-(4-methyl-1-piperidyl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-2-(4-methylthiazol-5-yl)-4-[3-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-4-[(3-methylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-[(3R)-3-methylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-[4-(hydroxymethyl)-1-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;4-[5-chloro-2-(4-methylthiazol-5-yl)-6-oxo-1H-pyrimidin-4-yl]-1,4-diazepan-2-one;5-chloro-4-(3,3-difluoro-1-piperidyl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-[3-(hydroxymethyl)-1-piperidyl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-[(3S)-3-methylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-2-(4-methylthiazol-5-yl)-4-piperazin-1-yl-1H-pyrimidin-6-one;5-chloro-2-(4-ethylthiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;5-chloro-2-(3-methyl-1H-pyrazol-4-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;5-chloro-2-(4-methylthiazol-5-yl)-4-[3-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-methylthiazol-5-yl)-4-[(3R)-3-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;5-chloro-4-tetrahydropyran-4-yl-2-[4-(trifluoromethyl)thiazol-5-yl]-1H-pyrimidin-6-one;5-chloro-4-[3-isopropylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-[(3S)-3-isopropylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-tetrahydropyran-4-yl-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;5-chloro-2-(2-methylpyrazol-3-yl)-4-tetrahydropyran-4-yl-1H-pyrimidin-6-one;5-chloro-2-(5-methyl-1H-pyrazol-4-yl)-4-morpholino-1H-pyrimidin-6-one;5-chloro-4-morpholino-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;5-chloro-4-[2-methylpiperazin-1-yl]-2-(5-methyl-1H-pyrazol-4-yl)-1H-pyrimidin-6-one;5-chloro-4-[(2R)-2-methylpiperazin-1-yl]-2-(5-methyl-1H-pyrazol-4-yl)-1H-pyrimidin-6-one;5-chloro-4-[3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-6-one;5-chloro-4-[(3R)-3-methylmorpholin-4-yl]-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-6-one;5-chloro-4-[3-methylmorpholin-4-yl]-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;5-chloro-4-[(3R)-3-methylmorpholin-4-yl]-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;5-chloro-4-[2-methylpiperazin-1-yl]-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;5-chloro-4-[(2R)-2-methylpiperazin-1-yl]-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;5-chloro-4-[3-methylmorpholin-4-yl]-2-pyrazolo[1,5-a]pyridin-3-yl-1H-pyrimidin-6-one;5-chloro-4-[(3R)-3-methylmorpholin-4-yl]-2-pyrazolo[1,5-a]pyridin-3-yl-1H-pyrimidin-6-one;5-chloro-4-[2-methylpiperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-6-one;5-chloro-4-[(2R)-2-methylpiperazin-1-yl]-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-6-one;5-chloro-4-(6,6-difluoro-1,4-diazepan-1-yl)-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;5-chloro-2-(5-chloro-1H-pyrazol-4-yl)-4-[(2R)-2-methylpiperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-4-(6,6-difluoro-1,4-diazepan-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrimidin-6-one;5-chloro-4-(2,2-dimethylpiperazin-1-yl)-2-[5-(trifluoromethyl)-1H-pyrazol-4-yl]-1H-pyrimidin-6-one;5-chloro-4-[2-methylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-[(2R)-2-methylpiperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-2-(3-methylisoxazol-4-yl)-4-[(2R)-2-methylpiperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-4-[3-methylmorpholin-4-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-[(3R)-3-methylmorpholin-4-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-(6,6-difluoro-1,4-diazepan-1-yl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-2-(5-chloro-1H-pyrazol-4-yl)-4-[3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;5-chloro-2-(5-chloro-1H-pyrazol-4-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-methylthiazol-5-yl)-4-[2-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-4-[2-(difluoromethyl)piperazin-1-yl]-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-4-(6-fluoro-1,4-diazepan-1-yl)-2-(4-methylthiazol-5-yl)-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-methylpiperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2R)-2-methylpiperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-4-[2-methylpiperazin-1-yl]-2-(2-methylpyrazol-3-yl)-1H-pyrimidin-6-one;5-chloro-4-[(2R)-2-methylpiperazin-1-yl]-2-(2-methylpyrazol-3-yl)-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-(6,6-difluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-one;5-chloro-2-(2-methylimidazol-1-yl)-4-[3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;5-chloro-2-(2-methylimidazol-1-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;5-chloro-2-(5-chloro-1H-pyrazol-4-yl)-4-(6,6-difluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-one;5-chloro-4-(6,6-difluoro-1,4-diazepan-1-yl)-2-[4-(trifluoromethyl)thiazol-5-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-(6-fluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2S)-2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2R)—R-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[6-fluoro-1,4-diazepan-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[(6S)-6-fluoro-1,4-diazepan-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[(6R)-6-fluoro-1,4-diazepan-1-yl]-1H-pyrimidin-6-one,or a salt or solvate thereof.
 26. A compound selected from:5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-methylpiperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2R)-2-methylpiperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-(6,6-difluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(trifluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-(6-fluoro-1,4-diazepan-1-yl)-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2S)-2-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[(2R)—R-(difluoromethyl)piperazin-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[6-fluoro-1,4-diazepan-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[(6R)-6-fluoro-1,4-diazepan-1-yl]-1H-pyrimidin-6-one;5-chloro-2-(4-chlorothiazol-5-yl)-4-[(6S)-6-fluoro-1,4-diazepan-1-yl]-1H-pyrimidin-6-one,or a salt or solvate thereof.
 27. A pharmaceutical compositioncomprising a compound according to claims 1 to 26, or a pharmaceuticallyacceptable salt or solvate thereof, in admixture with a pharmaceuticallyacceptable diluent or carrier.
 28. A compound as defined in any one ofclaims 1 to 26, or a pharmaceutically acceptable salt or solvatethereof, for use in therapy.
 29. A compound as defined in any one ofclaims 1 to 26, or a pharmaceutically acceptable salt or solvatethereof, for use in the treatment of a proliferative disorder.
 30. Acompound as defined in any one of claims 1 to 26, or a pharmaceuticallyacceptable salt or solvate thereof, for use in the treatment of cancer.31. A method of treating a proliferative disorder in a patient in needof such treatment, said method comprising administering to said patienta therapeutically effective amount of a compound according to claims 1to 26, or a pharmaceutically acceptable salt or solvate thereof.
 32. Themethod of claim 31, wherein the proliferative condition is cancer.
 33. Acombination comprising a compound, or a pharmaceutically acceptable saltor solvate thereof, as defined in any one of claims 1 to 26, with one ormore additional therapeutic agents.